Ruthenium-Catalyzed [2+2] Cycloaddition Reactions Between a 3-Aza-2-Oxa-Bicyclo[2.2.1]Hept-5-Ene and Unsymmetrical Alkynes

Ruthenium-catalyzed [2+2] Cycloaddition Reactions between a 3-Aza-2-oxa-bicyclo[2.2.1]hept-5-ene and Unsymmetrical Alkynes

Robin Durham

A Thesis presented to The University of Guelph

In partial fulfilment of requirements for the degree of Master of Science in Chemistry

Guelph, Ontario, Canada

ABSTRACT

RUTHENIUM-CATALYZED [2+2] CYCLOADDITION REACTIONS BETWEEN A 3-AZA-2-OXABICYCLO[2.2.1]HEPT-5-ENE AND UNSYMMETRICAL ALKYNES

Robin Lindsey Durham Advisor: University of Guelph, 2011 Professor W. Tam

This thesis is an investigation of ruthenium-catalyzed [2+2] cycloaddition reactions of a 3- aza-2-oxabicyclo[2.2.1]hept-5-ene with unsymmetrical alkynes. Yields of up to 90% were obtained though regioselectivity was modest. Select cycloadducts could be separated and used to access a highly functionalized [3.2.0] bicyclic structure through reductive cleavage of the N-O bond. These ring-opened products displayed a chemical exchange phenomenon in 1D carbon

NMR and required characterization by 2D NMR techniques. In addition, a haloalkynylation reaction was found to occur when 1-iodo-2-phenylethyne and the 3-aza-2-oxabicyclo[2.2.1]hept-

5-ene were submitted to the cycloaddition conditions. An effort was made to optimize the reaction between 1-iodo-2-phenylethyne and norbornadiene in favour of the addition product.

Acknowledgements

It is my pleasure to thank everyone that made this thesis possible. First and foremost, I am grateful to my supervisor Dr. William Tam. The effects of your advice and encouragement are felt far beyond the laboratory. You provide an example of a teacher and a leader to emulate and aspire to.

I would also like to thank the members of my committee: Dr. Adrian Schwan, Dr.

Richard Manderville, and Dr. France-Isabelle Auzanneau for providing their time and constructive criticism.

Moreover, I am indebted to my research group for their kind and diverse assistance. Thank you for making my life interesting and providing me with many, many, outlandish stories to tell. I fear my days will be boring without all of you!

Many thanks are also owed to Mickaël, the smart cookie down the hall. Your unconditional support and legendary patience were instrumental in the completion of this thesis.

Finally, I would like to thank my friends and family. You have gone through this experience with me, you knew I could do it, and you told me so. For this I am extremely grateful.

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Table of Contents Acknowledgements iii List of Abbreviations v List of Tables vii List of Figures viii List of Schemes x Chapter 1: Introduction 1.1.General Introduction 2 1.2.[2+2] Cycloadditions 3 1.2.1. Photochemical [2+2] Cycloadditions 3 1.2.2. Lewis Acid Catalyzed [2+2] Cycloadditions 6 1.2.3. Transition Metal-Catalyzed [2+2] Cycloadditions 9 1.2.4. Ruthenium-Catalyzed [2+2] Cycloadditions 12 1.3.Remote Substituent Effects 18 1.4.The 3-aza-2-oxabicyclo[2.2.1]hept-5-enes 28 1.5.Scope of Thesis 39 Chapter 2: Results and Discussion 2.1. Results and Discussion 42 2.2. Significance and Application 53 Chapter 3: Optimization of a Haloalkynylation Reaction 3.1. Introduction 58 3.2. Results and Discussion 60 3.3. Recent Developments in the Field 63 3.4. Conclusions 65 Chapter 4: Experimental 68 References 87

List of Abbreviations

Ac Acetyl APT Attached proton test Ar Aryl BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl BOC Tert-butoxycarbonyl Bn Benzyl Bu Butyl nBu Butyl (straight chain) COD 1,5-cyclooctadiene cot 1,3,5,7-cyclooctatetraene Cp Cyclopentadienyl Cp* 1,2,3,4,5-pentamethylcyclopentadienyl Cy Cyclohexyl mCPBA m-chloroperbenzoic acid DCE 1,2-dichloroethane DMF N,N-dimethylformamide Et Ethyl FMO Frontier molecular orbital HCOSY 1H-1H correlation spectroscopy HMBC Heteronuclear multiple bond correlation HOMO Highest occupied molecular orbital HSQC Heteronuclear single quantum coherence Hz Hertz IR Infrared LUMO Lowest unoccupied molecular orbital Me Methyl mg Milligram mm Millimole NMR Nuclear magnetic resonance

NOE Nuclear Overhauser effect NOESY Nuclear Overhauser effect spectroscopy Nu Nucleophile OTBS Tert-butyldimethylsilyl OTf Triflate Ph Phenyl ppm Parts per million iPr iso-propyl

Rf Retention factor THF Tetrahydrofuran Tol Tolyl

List of Tables

Title Page

Table 1. Cp*Ru(COD)Cl – catalyzed [2+2] cycloadditions of norbornene and 15 norbornadiene with aliphatic and aromatic internal alkynes

Table 2. Results of ruthenium-catalyzed [2+2] reactions with different 44 unsymmetrical

Table 3. Catalyst optimization for Ru-catalyzed haloalkynylation between 23 62 and 117s

Table 4. Attempts to optimize the solvent system for the Ru-catalyzed 63 haloalkynylation between 23 and 117s

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List of Figures

Title Page

Figure 1. Natural products containing small ring systems 2

Figure 2. Orbital interactions in the thermal [2+2] cycloaddition of ethene 4

Figure 3. Orbital interactions in the photochemical [2+2] cycloaddition of 4 ethene

Figure 4. Bicyclic alkenes used in the first examples of Ru-catalyzed [2+2] 13 cycloaddition reactions

Figure 5. Electron delocalization to the developing σ bond in the Cieplak model 20

Figure 6. Copper complexes formed by1,6-dienes with a remote oxygen 22 functionaility

Figure 7. Transition states leading to the major and minor regioisomers in the Ru-catalyzed [2+2] cycloaddition of a 2-substituted norbornene and an 26 unsymmetrical alkyne

Figure 8. Interactions between orbitals at C2 and C6 of 2-substituted 27 norbornene

Figure 9. Carbocyclic nucleosides formed from a ring opening reaction of a 29 3-Aza-2-oxobicyclo [2.2.1] hept-5-ene

Figure 10. Exo versus endo cycloadducts 45

Figure 11. 1H NMR of cycloadduct 119c 46

Figure 12. 13C NMR of cycloadduct 119c 46

Figure 13. Using gradient NOESY experiments to distinguish the regioisomers 47

Figure 14. NOSEY experiment showing an NOE between Ha and Hf of 119c 48

Figure 15. NOSEY experiment showing an NOE between Hc and HJ of 119c 48

Figure 16. The HCOSY spectrum demonstrates that H and H as well as H and a b c 49 Hd are on adjacent carbons

Figure 17. Natural products containing a [3.2.0] hetpane skeleton 49

Figure 18. Five carbons of compound 123 are virtually undetectable by 1D 13C 51 NMR

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Figure 19. A carbon unseen on the 1D projection is detected in an HSQC of 52 compound 123

Figure 20. Products of the Ru-catalyzed [2+2] cycloadditions of norbornadiene 59 and 1-iodo-2-phenylethyne

List of Schemes

Title Page

Scheme 1. Photochemical [2+2] cycloaddition of cyclohexanone and isobutene 5

Scheme 2. Photochemical [2+2] of cyclopentanone with either cis or trans 1,2- 6 dichloroethane Scheme 3. Lewis acid-catalyzed [2+2] cycloaddition of methyl propiolate and 7 trans-2-butene Scheme 4. Use of a 1,1-disubstituted olefin results in the formation of ene 7 adducts

Scheme 5. Asymmetric Lewis acid-catalyzed [2+2] using a Ti(IV) complex 8

Scheme 6. Asymmetric [2+2] cycloaddition through chelation control 8

Scheme 7. Ni-catalyzed cyclodimerization of 1,3-butadiene 9

Scheme 8. Ni-catalyzed [2+2] cycloaddition of cyclopropyl norbornene 10

Scheme 9. Ni-catalyzed [2+2] cycloaddition of 7-oxabenzonorbornene 11

Scheme 10. Co-catalyzed [2+2] cycloaddition of 7-oxabenzonorbornene 11 Scheme 11. Iron-catalyzed [2+2] cycloaddition of butadiene and ethene 12

Scheme 12. [2+2] cycloaddition of norbornene and dimethy 14 lacetylenedicarboxylate in the presence of Ru(cod)(cot)

Scheme 13. Plausible mechanism for ruthenium catalyzed [2+2] cycloaddition 17 with a Cp*RuCl(cod) catalyst Scheme 14. Electrophilic epoxidation of 7-methylenenorbornanes show a 18 reversal in facial selectivity

Scheme 15. Methyllithium addition reactions show a reversal in π-face 19 selectivity based on C2 and C3 substituents

Scheme 16. The Cu(I)-catalyzed [2+2] photocycloaddition of 1,6-diene 51 does 21 not occur

Scheme 17. The Cu(I)-catalyzed photochemical [2+2] cycloaddition of 1,6- dienes 22

Scheme 18. Remote substituent effects on the oxymercuration of 2-substituted 23 norbornenes

Scheme 19. Remote substituent effects on ruthenium-catalyzed [2+2] 24 cycloadditions of 2-substituted norbornenes

Scheme 20. Regioselectivity of Pauson-Khand [2+2+2] reactions of 2- 25 substituted norbornenes

Scheme 21. Modification of 3-aza-2-oxabicyclo[2.2.1]heptanes 29 Scheme 22. Chemical transformations involving the alkene component of 31 3-aza-2-oxabicyclo[2.2.1]hept-5-enes

Scheme 23. Acid-mediated ring opening with subsequent rearrangement forms 32 hydroxyl amine 1,2-cis cyclopentene product

Scheme 24. Palladium-catalyzed ring opening with an indium additive forms 32 three cyclopenetene diastereomers

Scheme 25. Lewis-acid catalyzed ring opening of bicyclic alkene 69 with 33 primary, secondary, and tertiary alcohols

Scheme 26. Copper (II) catalyzed nucleophilic ring opening using Grignard or 34 Organozinc reagents

Scheme 27. The nucleophilic ring opening of bicyclic alkene 97 with a cationic 35 and neutral ruthenium catalyst

Scheme 28. Rhodium(I)-catalyzed ring opening of bicyclic alkene 97 with 35 arylboronic acids

Scheme 29. Oxidative cleavage of C=C bond using mild ruthenium (III) chloride 36 catalyst conditions

Scheme 30. Metathesis reaction of bicyclic alkene 104 with Grubb’s 2nd 37 generation catalyst

Scheme 31. Di-hydroxylation of heterobyciclic alkene 107 in the synthesis of 37 synthetic nucleoside analogue 108

Scheme 32. Alkylidene cyclopropanation heterobicyclic alkene 109 using a 38 platinum/SPO complex

Scheme 33. [3+2] cycloaddition of heterobicyclic alkene 97 and azides to form 39 exo triazolines with subsequent conversion to aziridine

Scheme 34. Synthesis of 3-aza-2-oxabicyclo[2.2.1]hept-5enes through a hetero- 42 Diels-Alder reaction

Scheme 35. General synthesis of the unsymmetrical alkynes 42

Scheme 36. Ring-opening of the [2+2] cycloadducts through reductive cleavage 50 of the N-O bond

Scheme 37. Possible electrostatic interactions in the transition state leading to the 54 major regioisomeric product

Scheme 38. Ring expansion of a cyclobutene to produce an 8-membered ring 55

Scheme 39. Simmons-Smith cyclopropanation of a [2+2] cycloadduct and 55 possible cleavage sites

Scheme 40. Potential treatment of the cycloadducts of 56 3-aza-2-oxobicyclo[2.2.1]hept-5-ene 97

Scheme 41. Reaction with alkyne 117 appears to produce addition products 58 alongside [2+2] cycloadducts

Scheme 42. Ru-catalyzed [2+2] cycloadditions of norbornadiene and various 59 alkynyl halides

Scheme 43. Synthesis of 1-iodo-2-phenylethyne from phenylacetylene 60

Scheme 44. The palladium-catalyzed bromoalkynylation of norbornene 64

Scheme 45. Palladium-catalyzed haloalkynylation of norbornene with various 65 alkynyl halides

Scheme 46. Palladium-catalyzed reaction of phenylethynyl bromide with 65 cyclootene

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Chapter 1: Introduction

1. Introduction

Synthetic organic chemistry is an important and attractive area of research. The investigation and development of new synthetic strategies is particularly significant as these methods can later be applied to the construction of desirable natural products.1

Ring systems are a key feature of these natural products and as a result an in depth knowledge of their synthesis is important. Natural products containing small rings are significant not only for their pharmacological or industrial applications but also because their structural challenges provide the opportunity to apply novel methodology. The natural product (+)-Grandisol is used agriculturally to help control pests while cyclobutadithymine has demonstrated protective properties against UV-A irradiation

(Figure 1).2, 3 In addition, U-106305 has not only demonstrated the ability to inhibit the cholesteryl ester transfer protein reaction but was also used to showcase Charette’s asymmetric cyclopropanation.4

1, 2, 3 Figure 1. Natural products containing small ring systems.

Although all of the small ring systems are of note synthetically, the study of cyclobutane and cyclobutene rings is of particular interest. As well as being present in a number of natural products, these moieties possess a large amount of ring strain. Relief of this strain provides a driving force for the relatively facile cleavage of these rings, providing access to alternate structures including larger ring systems.5 An effective and commonly used strategy for the formation of cyclobutene rings is the [2+2] cycloaddition reaction.

1.2. [2+2] Cycloadditions

The [2+2] cycloaddition reaction obtains its significance in organic synthesis from its ability to create two carbon-carbon bonds with concomitant installation of up to four new stereogenic centres.6 This potentially highly useful synthetic reaction can be promoted photochemically, mediated by Lewis acids, or catalyzed by transition metals.

1.2.1. Photochemical [2+2] Cycloadditions

According to the Woodward-Hoffman rules, a photochemical [2+2] cycloaddition is symmetry allowed, while the equivalent thermal reaction is symmetry forbidden.7

These statements can be expanded by examining the frontier molecular orbital (FMO) theory by Kenichi Fukui. They can be illustrated using the [2+2] cycloaddition of two ethene molecules. In a thermal reaction the molecules react in their ground states so the π orbital (HOMO) of one ethene molecule would be expected to interact with the π* orbital

(LUMO) of the other (Figure 2). However, since the orbitals on the top set of carbon atoms are of opposite signs, the overlap does not lead to a bonding interaction.

Therefore, this reaction is unlikely to occur through a concerted process and is said to be symmetry forbidden.

This is not the case for the photochemical reaction. During this process, a molecule of ethene absorbs a photon of light; this promotes one of its electrons from the π to the π*orbital. The HOMO of the excited state ethene is now the π* orbital and overlap between this new HOMO and the LUMO of a ground state ethene creates a bonding interaction (Figure 3). For that reason, this reaction is said to be symmetry allowed and can proceed through a concerted pathway.7

Figure 2. Orbital interactions in the thermal [2+2] cycloaddition of ethene.7

Figure 3. Orbital interactions in the photochemical [2+2] cycloaddition of ethene.7

When the ethene molecules are replaced with unsymmetrical alkenes, the photochemical [2+2] cycloaddition can produce two regioisomers, the head-to-head and the head-to-tail products.6 For instance, irradiation of cyclohexanone 1 and isobutene 2 yields a head-to-head isomer 3 in addition to the head-to-tail product 4 (Scheme 1). The regioselectivity in this reaction is generally explained through electrostatic interactions.

During the cycloaddition, the head-to-tail orientation maximizes the electrostatic interactions between the excited state enone and the ground state alkene. This interpretation was verified when high regioselectivity was observed in reactions involving highly polarized enones and alkenes. Other factors affecting regioselectivity include the steric interactions between substituted enones and alkenes as well as solvent polarity and temperature.6

Scheme 1. Photochemical [2+2] cycloaddition of cyclohexanone and isobutene.6

Though the photochemical [2+2] cycloaddition is a symmetry allowed process, the reaction is generally stepwise and proceeds through discrete radical intermediates.

This complicates the stereoselectivity of a photochemical addition of an acyclic alkene to a cyclic enone. The rotational freedom in the long-lived 1,4-diradical intermediate results in loss of stereochemistry during the reaction. Regardless of whether the cis or trans alkene is used, the irradiation of cyclopentanone with 1,2-dichloroethane produces the same four cis photoadducts (Scheme 2). In order to avoid this loss of stereochemistry, a

5 cyclic alkene with a ring size of five or less may be used. The stereochemistry of the photocycloaddition can also be influenced by the presence of a pre-existing stereogenic centre. For example, a stereocentre on the ground-state alkene will cause the excited- state enone to add to the less sterically hindered face.6

One of the major disadvantages in the photochemical [2+2] cycloaddition is the low selectivity obtained in some systems. However, this problem can be minimized through the use of the intramolecular reaction. The geometric constraints placed on the intermediates during ring closure result in highly stereoselective cycloadditions while regioselectivity is also much higher and more predictable.6

Scheme 2. Photochemical [2+2] of cyclopentanone with either cis or trans 1,2- dichloroethane.6

1.2.2. Lewis Acid Catalyzed [2+2] Cycloadditions

Several examples exist in the literature of [2+2] cycloadditions catalyzed by

Lewis acids. Early investigations include the aluminum trichloride-catalyzed reactions studied by Snider and coworkers. This research revealed that alkenes could undergo a stereoselective [2+2] cycloaddition with propiolate esters in the presence of aluminum trichloride. For example, methyl propiolate 5 reacted stereoselectively with cis-2-butene

6 to produce cis-3,4-dimethylcyclobutenecarboxylate 7 (Scheme 3). When additional

1,2-disubstituted and monosubstituted alkenes were investigated, ene adduct by-products were observed in addition to the desired cycloadducts.8

Scheme 3. Lewis acid-catalyzed [2+2] cycloaddition of methyl propiolate and cis-2- 8 butene.

Snider and coworkers later expanded the scope of the Lewis acid-catalyzed cycloaddition of methyl propiolate. A larger variety of alkenes was included and ethylaluminum dichloride was used as a catalyst to accommodate acid sensitive starting materials. However, 1,1-disubstituted, trisubstituted, and tetrasubstituted olefins provided the ene adducts only (Scheme 4).9

9 Scheme 4. Use of a 1,1-disubstituted olefin results in the formation of ene adducts.

Lewis acid-catalyzed [2+2] cycloadditions can be used to synthesize asymmetric cyclobutanes through the incorporation of chiral ligands into the metal complex. When styrenes are treated with 1,4-benzoquinones and a Ti(IV) complex, the butane cycloadducts are generally produced in good yields and with high enantioselectivity

(Scheme 5). Despite this, the products formed in these reactions remain highly

7 dependent upon the temperature and the substitution pattern of the styrene and benzoquinone substrates. In some cases a benzofuran structure was produced either exclusively or as a side-product.10

Scheme 5. Asymmetric Lewis acid-catalyzed [2+2] using a Ti(IV) complex.10

Chelation control, analogous to that used in cyclocondensation, allylation, and aldol reactions, is another strategy of obtaining chiral [2+2] cycloadducts. A highly diastereoselective cycloaddition occurs when an α- or β-benzyloxy aldehyde and a ketene are subjected to a chelating Lewis acid. A titanium or magnesium Lewis acid forms a conformationally rigid chelate with the α- or β-benzyloxy aldehyde and confers a large facial bias. This is thought to be the source of the selectivity. Accordingly, MgBr2·Et2O provides asymmetric β-lactone 8 from (S)-9 and ketene 10 (Scheme 6).11

Scheme 6. Asymmetric [2+2] cycloaddition through chelation control.11

1.2.3. Transition Metal-Catalyzed [2+2] Cycloadditions

Though [2+2] cycloadditions have been promoted using light and Lewis acids, these reactions are mainly limited to substrates bearing polar functional groups.

Substrates without these polar substituents generally necessitate the use of harsh conditions such as high temperatures and pressures. Transition metal catalysts provide a response to the synthetic challenge of cycloaddition reactions which are difficult to achieve or theoretically forbidden. Complexation of the transition metal to the previously unreactive olefin, alkene, or diene, causes temporary polarization of the substrate and enhances the reactivity. As a result transition metal catalysts provide rate enhancement and the opportunity for highly selective cycloadditions.12

An early example of transition metal catalysis in [2+2] cycloadditions is the cyclodimerization of butadiene. In the presence of a zerovalent nickel complex, 1,3- butadiene 11 will undergo a [2+2] dimerization to cis-1,2-divinylcyclobutane 12 though formation of cyclooctadiene 13 and vinylcyclohexene 14 also occurs (Scheme 7).13 As compound 11 was shown to provide the useful cyclooctadiene ligand through a Cope rearrangement, this cyclobutane structure has been previously synthesized through multi- step pathways and photosensitized dimerization.14 The transition metal-catalyzed route is an improvement on these methods and provides the [2+2] cycloadduct with an increased rate and higher yields.13

13 Scheme 7. Ni-catalyzed cyclodimerization of 1,3-butadiene. 9

Strained alkenes have also been shown to undergo [2+2] cycloadditions under the influence of Ni(0) catalysts. Cyclopropanated norbornene 15 undergoes a nickel- catalyzed cycloaddition with methyl acrylate 16 to provide cycloadducts 17 and 18 in

72% yield and a ratio of 78:22 (Scheme 8).15 This reaction demonstrated the selectivity available with transition metal catalysts. Though bicyclic alkenes and electron deficient olefins were known to undergo other reactions like the homo-Diels-Alder, these conditions provided the [2+2] cycloadducts exclusively. In addition, these reactions produced exo cycloadducts only, indicating a high degree of stereoselectivity.15

Scheme 8. Ni-catalyzed [2+2] cycloaddition of cyclopropyl norbornene.15

As well as the above reactions of olefins, nickel complexes have also been shown to catalyze [2+2] cycloadditions of bicyclic alkenes with acetylenes.16 The nickel- phosphine complex [Ni(PPh3)2Cl2]/PPh3 with the addition of Zn powder catalyzes the

[2+2] cycloaddition of 7-oxabenzonorbornadiene with various alkynes to yield the corresponding exo-cycloadducts in good yields (Scheme 9). Lower yields were obtained when the alkyne lacked an electron-withdrawing group; however when the alkyne possessed one or more of these functionalities, yields of up to 90% were observed.

Though these disubstituted alkynes underwent the [2+2] cycloaddition smoothly, monosubsituted alkynes such as phenylacetylene were more prone to a [2+2+2] cyclotrimerization.16

Scheme 9. Ni-catalyzed [2+2] cycloaddition of 7-oxabenzonorbornene.16

After investigating the Ni-catalyzed cycloaddition, Cheng and coworkers found that a similar system involving cobalt also catalyzes the [2+2] reaction between bicyclic

17 alkenes and acetylenes. Under the influence of the cobalt complex [CoI2(PPh3)2], triphenylphosphine, and zinc powder in toluene, 7-oxabenzonorbornene will undergo a

[2+2] cycloaddition with a variety of alkynes (Scheme 10). Though the cobalt- and nickel-catalyzed reactions are similar, the types of alkynes compatible with each transition metal are different. The Co-catalyzed cycloaddition gives high yields of the cyclobutene product with monosubstitued and dialkylacetylenes which produced low yields using the nickel catalyst. As a result, these two transition metal catalysts seem to complement each other.17

Scheme 10. Co-catalyzed [2+2] cycloaddition of 7-oxabenzonorbornene.17

It has recently been demonstrated that iron complexes are also capable of promoting [2+2] cycloadditions. The bis(imino)pyridine iron butadiene compounds of

i the type (RPDI)Fe(N2)2 (where PDI = 2,6-(2,6-R2-C6H3N=CMe)2C5H3N and R= Me or Pr) were found to catalyze the intermolecular cycloaddition between butadiene, 11, and ethene, 19, to form vinylcyclobutane 20 (Scheme 11).18 Use of a butadiene with one methyl group led to a 1,4-addition product instead of the desired cyclobutane while two methyl groups resulted no reaction. Thus the scope of this reaction is fairly limited.

However, the researchers were able to isolate the iron metallocycle intermediate and establish reductive elimination as the rate-limiting step. Understanding the mechanism could allow catalyst development and future expansion of the scope.18

Scheme 11. Iron-catalyzed [2+2] cycloaddition of butadiene and ethene.18

1.2.4. Ruthenium-Catalyzed [2+2] Cycloadditions

A number of characteristics make ruthenium an important transition metal in organic synthesis.19 Ruthenium has the largest range of oxidation states of any element on the periodic table spanning from -2 to +8 and this allows for the formation of a variety of ruthenium complexes. These ruthenium complexes display properties such as low redox potential, high electron transfer ability, high affinity for heteroatoms, and the ability to function as a Lewis acid. The metallic species and intermediates formed by

12 ruthenium such as oxo-metals, metal carbene complexes and metallacycles offer distinctive reactivity. Metallacycles are carbocyclic systems containing at least one metal element. As a result they contain at least two reactive carbon-metal bonds and function as key intermediates in a number of carbon-carbon bond forming reactions, including the ruthenium-catalyzed [2+2] cycloaddition.19

Ruthenium complexes were first found to be effective catalysts for [2+2] cycloaddition reactions by Mitsudo during the 1970’s.20 The reaction of dimethylacetylene dicarboxylate with bicyclic olefins such as norbornene 21, endo-5,6- dicarbomethoxynorbornene 22, norbornadiene 23, 2,3-dicarbomethoxynorbornadiene 24, benzonorbornadiene 25, 7-oxabenzonorbornadiene 26, and 2,3-dicarbomethoxy-1- methyl-7-oxabenzonorbornadiene 27 constitute the initial reported cases of Ru-catalyzed

[2+2] cycloadditions (Figure 4). Reaction conditions included a catalytic amount of

RuH2(PPh3)4, equimolar amounts of alkyne and bicyclic alkene in benzene, a temperature of 80-100 °C, and a time of 6-24 h. The highly stereoselective reactions furnished only the exo cycloadduct in modest to excellent yields depending on the alkene.20

Figure 4. Bicyclic alkenes used in the first examples of Ru-catalyzed [2+2] cycloaddition reactions.20

After further investigation, suitable catalysts for the [2+2] cycloaddition included

RuH2(PPh3)4, RuH2(CO)[PPh3]3, and Ru(cod)(cot)/PBu3. For example, quantitative yields

(99%) could be obtained in the [2+2] cycloaddition of norbornene 21 and dimethyl acetylenedicarboxylate 28 using the Ru(cod)(cot) catalyst with a PBu3 additive (Scheme

12). However, each of these catalysts still required the presence of strong electron- withdrawing groups, such as carbomethoxy groups, on the alkyne moiety which greatly limited the scope of the reaction.21

Scheme 12. [2+2] cycloaddition of norbornene and dimethylacetylenedicarboxylate in the presence of Ru(cod)(cot).12

The Mitsudo group subsequently discovered that norbornene derivatives underwent successful [2+2] cycloaddition with a wide variety of aliphatic and aromatic alkynes in the presence of the catalyst Cp*RuCl(cod) (Cp* = 1,2,3,4,5- pentamethylcyclopentadienyl) (Table 1). Using this catalyst, Mitsudo put forward a mechanism for the reaction in which the neutral [Cp*RuCl] species, rather than the positively charged [Cp*Ru]+ moiety, was the active catalytic species. This was supported by results from an experiment, which involved deliberate generation of the cationic

[Cp*Ru]+ species through addition of silver triflate to Cp*RuCl(cod); the yield of the

[2+2] cycloadduct was reduced by more than half.21 With the neutral species functioning

14 as the active catalyst instead of a cationic species, it can be deduced that ester substituted alkynes (electron poor) would be more reactive towards cycloaddition than alkyl substituted or terminal alkynes (electron rich). As well as highlighting the catalytic species and predicting reactivity, Mitsudo’s reaction mechanism provides insight into the stereoselectivity of the reaction. Though both endo and exo cycloadducts are theoretically possible, exclusive formation of the exo adducts has been seen in ruthenium catalyzed [2+2] cycloadditions.12

Table 1. Cp*Ru(COD)Cl – catalyzed [2+2] cycloadditions of norbornene and norbornadiene with aliphatic and aromatic internal alkynes.

Alkene Entry R1 R2 Time (h) Yield (%) A 1 Ph Ph 15 88 A 2 Ph Me 15 87 A 3 C5H11 C5H11 20 40 A 4 Et CH(OEt)2 15 62 A 5 Ph CO2Et 15 60 A 6 Me CO2Me 17 79 B 7 CO2Me CO2Me 24 37 B 8 Me CO2Me 24 87 B 9 Ph CO2Et 24 74 B 10 Ph Ph 120 23 B 11 Ph H 16 44a a B 12 n-C8H17 H 40 23 a B 13 n-C10H21 H 40 23 aYield determined by gas chromatography

According to Mitsudo, the ruthenium-catalyzed [2+2] cycloaddition of bicyclic alkenes and alkynes begins with the formation of the catalytically active [Cp*RuCl] species through dissociation of the labile cod ligand (Scheme 13).21 Subsequently, intermediate π-complex 30 is formed after coordination of the bicyclic alkene and alkyne to ruthenium. The alkene, alkyne, Cp*, and Cl ligands attatched to Ru can be arranged in a variety of ways providing four possible π-complexes. Computational studies have shown that complex 30 is the lowest in energy, and thus the most favourable, with Cl and alkyne located above C2 and C3 of the bicyclic alkene and the Cp* ligand oriented away from the alkene.22 In addition, the ruthenium itself is coordinated to the exo face of the bicyclic alkene as hyperconjugative effects are considered to provide the exo face with increased π-electron density compared with the endo face of the molecule.23 The following step in the catalytic cycle is the oxidative cyclization of Ru by the coordinated alkene and alkyne which leads to the high-energy metallacyclopentene 31. Theoretical studies indicate that the formation of this ruthenacyclopentene intermediate is the rate- determining step of the catalytic process.22 Though there have been no successful attempts to isolate this intermediate due to its highly unstable nature, analogous nickel and iridium structures have been isolated and confirmed by x-ray crystallography.24, 25

Next, reductive elimination simultaneously regenerates the catalytically active

[Cp*RuCl] and furnishes the exo-[2+2] cycloadduct 32.21

Scheme 13. Plausible mechanism for ruthenium catalyzed [2+2] cycloaddition with a Cp*RuCl(cod) catalyst.21

The mechanism discussed above describes the reaction of symmetrical alkenes.

The use of unsymmetrical bicyclic alkenes and alkynes provides the possibility for a regioselective [2+2] cycloaddition. Portions of the starting material removed from the site of the reaction, or remote substituents, can be seen to affect the preferential formation of one isomer over another in this and other reactions.

1.3 Remote Substituent Effects

The influence of remote substituents in π-face diastereoselection during nucleophilic and electrophilic addition reactions has been the subject of extensive study.26

One such investigation explores electrophilic additions to 2,3-endo,endo-7- methylenenorbornanes. The electrophilic epoxidation of the diethyl compound 37 shows a moderate π-face stereoselectivity (Scheme 14).

Scheme 14. Electrophilic epoxidation of 7-methylenenorbornanes show a reversal in facial selectivity.26

Though the two π- faces of the 7-methylenenorbornane compound 37 are sterically equivalent, the results show that the electrophile, m-chloroperbenzoic acid, attacks predominantly from the anti-face. This results in a product ratio of 70:30 in favour of the

18 anti-approach epoxide 38. This facial preference is reversed when the electron-donating alkyl groups at the 2, 3 positions are exchanged for electron-withdrawing ester substituents. The mCPBA now approaches preferentially from the syn-face and the syn- approach epoxide 39 is now the major product. The π-facial selectivity of this electrophilic addition has been completely reversed by altering the electronics of remote substituents.26

This phenomenon is not unique to electrophilic additions. Another study found a similar change in stereochemical preference through a nucleophilic addition reaction.27

When methyllithium is added to bicyclo[2.2.1]heptane compound 42, it results in a 90% selectivity for the anti-addition product 43 (Scheme 15). A similar methyllithium reaction provides exclusive formation of the syn-addition product 44.27 Reaction A differs from reaction B in that the starting material 45 possesses an electron-withdrawing modification at the C2 and C3 positions. This results in a higher percentage of syn-attack

27 by the nucleophile CH3Li.

Scheme 15. Methyllithium addition reactions show a reversal in π-face selectivity based on C2 and C3 substituents.27

Stereochemical selectivities of this type have been justified using the Cieplak hyperconjugative model. According to the Cieplak model, facial selectivity occurs when electron delocalization between the σ orbital of the electron-rich antiperiplanar bond and the σ* orbital of the developing bond stabilizes one of the transition states (Figure 5).26

A compound such as 48, with electron-withdrawing groups at the C2,C3 positions, has a

C1-C6 bond that is more electron rich than the C1-C2 bond and this leads to a preference for syn attack by the nucleophile. On the other hand, the electron-donating groups at carbons 2 and 3 in 49 cause the C1-C2 bond to be more electron rich and this results in a higher prevalence of anti attack. This theory is applicable to both nucleophilic and electrophilic additions as hyperconjugation occurs between σ and σ* orbitals irrespective of where the bonding electrons originate.28

Figure 5. Electron delocalization to the developing σ bond in the Cieplak model.28

As well as influencing isolated reactions on sterically neutral substrates, remote substituent effects come into play in more complex situations. In an effort to complete the total synthesis of the marine prostanoid tricycloclavulone, researchers found that the reactivity and stereoselectivity of the photocycloaddition step was surprisingly dependant on remote substituents.29 The original synthetic approach envisaged access to

20 cyclobutane derivative 50 through the Cu(I)-catalyzed photocycloaddition from tetraene

51 (Scheme 16). However, no reaction was observed and the failure of the cycloaddition was attributed to the steric bulk of the substrate.

Scheme 16. The Cu(I)-catalyzed [2+2] photocycloaddition of 1,6-diene 51 does not occur.29

As previous investigations had demonstrated the impact of a remote hydroxyl group on the Cu(I)-catalyzed photochemical cycloaddition of 1,6-dienes, the group envisioned that a substrate such as 52 would undergo the desired reaction.29 Indeed, irradiation of triene 52 in the presence of CuOTf yielded cycloadduct 53 in moderate yield (Scheme

17). Compound 54 also led to the formation of cyclobutane 53 under the same condiditons, despite the presence of a bulky acetonide group. The reactivity of these substrates in comparison to their deoxy counterpart (51) clearly demonstrates that the remote oxygen moiety facilitates the cycloaddition, even overriding steric restrictions. In addition to bringing about the cycloadditions, the oxygen functionalities are responsible for the stereochemistry of the cycloadduct. The cycloaddition was found to occur from the same face as the oxygen functionality.29

Scheme 17. The Cu(I)-catalyzed photochemical [2+2] cycloaddition of 1,6-dienes. 29

It is likely that these cycloaddition proceeds through a tri-co-ordinated Cu complex

55 and 56 for 1,6-dienes 52 and 54, respectfully (Figure 6). This complex helps explain how both the reactivity and stereoselectivity can be controlled by a remote oxygen substituent.29

Figure 6. Copper complexes formed by 1,6-dienes with a remote oxygen functionality.29

In addition to the effect on stereoselectivity, the effect of remote substituents on the regioselectivity of nucleophilic and electrophilic additions to π-bonds has been the focus of various studies.30 One study by the Tam research group investigates remote substituent effects on regioselectivity in the oxymercuration of various 2-substituted norbornenes (Scheme 18).

Scheme 18. Remote substituent effects on the oxymercuration of 2-substituted norbornenes.30

Bicyclic olefins generally undergo oxymercuration to produce syn-addition products unlike monocyclic olefins which usually follow anti additions.30 In accordance with this, oxymercuration of all exo-2-substituted and endo-2-substituted norbornenes is highly stereoselective and gives only the syn-exo product. Two regioisomers can be formed in the syn oxymercuration of 2-substitued norbornene; Hg can end up on C5, as in regioisomer 57, or C6, as in regioisomer 58. The major regioisomer formed in all cases is 57 with regioselectivities of 1:1 to 14:1 being observed. On the whole, exo-2- substituted norbornenes give better regioselectivities than the corresponding endo-2- substituted norbornenes.30

Another Tam group study examines remote substituent effects on the regioselectivities of ruthenium-catalyzed [2+2] cycloadditions of 2-substituted norbornenes with an unsymmetrical alkyne (Scheme 19).31

Scheme 19. Remote substituent effects on ruthenium-catalyzed [2+2] cycloadditions of 2-substituted norbornenes.31

Although both the endo and exo cycloadducts are theoretically possible, these cycloadditions produced a mixture of the regioisomers of the exo-cycloadducts only.

Various substituents at the C2 position of the norbornenes give regioselectivities of 1.2:1 to 7.5:1. As with the previous study, the exo-2-substituted norbornenes display greater remote substituent effects and higher regioselectivities than the corresponding endo-2- substituted norbornenes. Substituents with an exocyclic double bond such as a ketone at the C2 position show the strongest remote substituent effect and give the highest regioselectivity.31

A third Tam group study investigated the regioselectivity of the Co-mediated

Pauson-Khand reaction of various 2-substituted norbornenes.32 Norbornenes with exo,

24 endo, and unsaturated substituents at the C2 position underwent Pauson-Khand [2+2+2] cycloadditions with alkyne 60 in the presence of Co2(CO)8 and a cyclohexylamine activator to provide cycloadducts 61 and 62 (Scheme 20).

Scheme 20. Regioselectivity of Pauson-Khand [2+2+2] reactions of 2-substituted norbornenes.32

Though the regioselectivities of 50:50 to 74:26 observed in these reactions were only moderate, a few key trends emerged. First of all, the exo-2-substituted norbornenes gave higher regioselectivity than the endo-2-substituted norbornenes. This corroborates the trends seen in the previous two studies where a larger remote substituent effect was provided by norbornenes bearing exo substitutents compared to their endo-substituted analogues. A second observation is that the norbornene with a ketone at C2 provided the highest regioselectivity. This coincides with what was seen in the study on Ru-catalyzed

[2+2] cycloadditions, that substrates with an exocyclic double bond at the C2 position displayed the strongest remote substituent effects.32 The fact that these trends are

25 observed in three different reactions provides important information about the electronic properties of 2-substituted norbornenes.

The relationship between remote substituents and regioselectivity in these studies becomes clear when the origin of the regioselectivity itself is investigated. For example, a ruthenium-catalyzed [2+2] cycloaddition between a bicyclic alkene and an unsymmetrical alkyne goes through one of two oxidative addition transition states depending on which regioisomer is formed (Figure 7).31

Figure 7. Transition states leading to the major and minor regioisomers in the Ru- catalyzed [2+2] cycloaddition of a 2-substituted norbornene and an unsymmetrical 31 alkyne.

According to computational analysis, the oxidative addition step is rate- determining for this reaction.22 Consequently, the regioselectivity observed in these reactions stems from small energy differences between the possible oxidative addition transition states. In each of the two transition sates Cb is more negative than Ca due to the electron-withdrawing properties of the ester substituent. In addition, the inductive effect of ruthenium places a partially negative charge on the adjacent carbon. Hence, C6 would be more negative than C5 in transition state 64 while C5 would tend to be more negative than C6 in 65. Transition state 64 is stabilized by favourable electrostatic interactions as the bond forming in 64 is between a positive C5 and a negative Cb.

Therefore, transition state 64 leads to the major regioisomer. According to computational analyses, C5 in transition state 65 is less negative than C6 in transition state 64. This results in reduced stabilization in transition state 65 which consequently leads to the minor regiosisomer.22

Though this explains the appearance of the major and minor regioisomer, it does not explain the differences in regioselectivity for the various 2-substituted norbornenes.

The previous studies on 2-substituted norbornene clearly indicate that the substituent at the C2 position is having an effect on carbons five and six with endo, exo, and unsaturated substituents all demonstrating different levels of this effect.31 This is an electronic effect that can be rationalized using a homoconjugation model. Norbornene possesses a bent geometry due to its bicyclic framework which orients the orbitals in such a way that through-space interactions are possible (Figure 8). A 2-substituted norbornene with a substituent Y could experience electron delocalization between the filled π (C5-

C6) orbital and the empty π*(C2-Y) or σ*(C2-Y) causing the C5-C6 bond to be polarized with C5 being partially positive and C6 partially negative.

Figure 8. Interactions between orbitals at C2 and C6 of 2-substituted norbornene.31

This affects the stability of the transition states leading to the different regioisomers and contributes to regioselectivity. The partial negative charge on C6 is not

27 favourable to bond formation between this carbon and the partially negative alkyne Cb.

This destabilizes the transition state, 64, which leads to the minor regioisomeric product.

The alternative transition state 65 does not experience such a destabilization. In fact, this polarization of the C5-C6 bond contributes to the favourable electrostatic interaction already present, making 65 even more favourable. In view of that, a stronger orbital interaction would increase the energy difference between the two transition states and, consequently, cause a greater regioselectivity.31

In addition to substituted norbornenes, other classes of unsymmetrical bicyclic alkene, such as the aza-2-oxabicyclo[2.2.1]hept-5-enes, can display remote substituent effects and result in the formation of different regioisomers.

1.4. The 3-aza-2-oxabicyclo[2.2.1]hept-5-enes

The 3-aza-2-oxabicyclo[2.2.1]heptenes are a group of heterobicyclic alkene which have been extensively investigated due to their utility as synthetic intermediates.

Synthesized through a nitroso hetero-Diels-Alder reaction, these relatively simple cycloadducts provide access to more complex molecular structures.33 Their unsymmetrical structure allows for the formation of a variety of cyclopentene stereoisomers which can then undergo further functionalization. Indeed, a category of natural products known as carbocyclic nucleosides, such as Neplanocin A 66,

Aristeromycin 67 and Noraristeromycin 68 (Figure 9), involve a ring opening reaction of a 3-aza-2-oxabicyclo[2.2.1]heptene containing substrate as an early step in their

28 synthesis. These nucleoside analogues have interesting pharmalogical properties such as effectiveness against DNA and RNA viruses.34

Figure 9. Carbocyclic nucleosides formed from a ring opening reaction of a 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene.34

Though rearrangements and other chemical reactions can also occur, heterobicyclic alkene 69 is generally modified in one of four ways (Scheme 21).35 These four categories consist of cleavage of the N-O bond, cleavage of the C-O bond, cleavage of the N-acyl bond, and modification of the alkene component.

Scheme 21. Modification of 3-aza-2-oxabicyclo[2.2.1]heptenes.35

The first of these four categories, reductive cleavage of the N-O bond, is a common method for derivatizing heterobicyclic alkene 69 and provides amino alcohol

36, 37 70. Widely used reagents include molybdenumhexacarbonyl ([Mo(CO)6]), catalytic hydrogenation, zinc in acetic acid, samarium diiodide,38 and titanocene (III) chloride.39

Examples that employ enzymatic,40 photochemical,41 and other chemical process to reductively cleave this bond are also present in the literature.42

The second area of structural modification of 69 is cleavage of the C-O bond to form compounds 71 and 72 where the stereochemistry depends on the method used.

These methods include: acid catalyzed ring-opening rearrangements;43 palladium and

Lewis-acid catalyzed ring-openings;44 copper-catalyzed Grignard or organozinc nucleophilic ring-opening reactions;45 ruthenium-catalyzed ring opening reactions with alcohols; 46 and rhodium-catalyzed ring opening reactions with arylboronic acids.47

The third category represents hydrolysis of the carbonyl group under mild conditions to yield compound 73.48 This allows removal of any chiral auxiliaries used to induce chirality during the acylnitroso hetero-Diels-Alder reaction.

In the final category, it is the alkene component of 69 which is modified to yield structures such as 74 or 75. A number of transformations have been carried out on the alkene moiety of related 3-aza-2-oxabicyclo[2.2.1]hept-5-ene system 76 (Scheme 22).

Examples include oxidative cleavage to give diacid compound 77, ring-opening cross- metathesis providing compounds 78a and 78b,49 dihydroxylation to yield diol 79,50 and alkylidene cyclopropanation resulting in compound 80.51 In addition, the dipolar

30 cycloaddition of alkene 76 with organic azides and nitrile oxides provides regioisomeric mixtures 81a, b, and 82a, b, respectively.52

Scheme 22. Chemical transformations involving the alkene component of 3-aza-2-oxabicyclo[2.2.1]hept-5-enes.35

With a general overview in hand, it is worthwhile to look at a number of these reactions in more detail. It was seen that ring-opened products of 69 can be formed through an acid-mediated ring-opening followed by a rearrangement.43 One study found that protonation of the oxygen of the heterobicycle with concentrated hydrochloric acid in dioxane produces a single diastereomer of the ring-opened product. Bicycle 83 underwent ring opening and subsequent rearrangement to form 1,2-cis compound 84 as a

31 chloride salt (Scheme 23). The final hydroxyl amine 1,2-cis cyclopentene product 85 is attained by quenching the reaction with a base in order to eliminate the salt.43

Scheme 23. Acid-mediated ring opening with subsequent rearrangement forms hydroxyl amine 1,2-cis cyclopentene product.43

Reactions catalyzed by palladium offer another approach to the ring opening of 3- aza-2-oxabicyclo[2.2.1]hept-5-ene and this method has been well established for the synthesis of cyclopentenes. The use of a palladium catalyst without any additives results in the exclusive formation of the 1,4-cis cyclopentene isomer in most cases.44(a)

However, in the presence of an indium additive, heterobicycle 86 can be ring-opened with a variety of substituted aldehydes to give three isomeric products (Scheme 24).

Though the 1,4-cis isomer is the major product in all cases, a mixture of 1,4-cis 87, 1,4- trans 88, and 1,2-trans 89 cyclopentene diastereomers was observed.44(a)

Scheme 24. Palladium-catalyzed ring opening with an indium additive forms

three cyclopenetene diastereomers.44(a)

Unlike palladium-catalyzed ring opening, the use of Lewis acid catalysts allows for the formation of different isomers as the major product of the ring-opening of bicyclic alkene 76.44(c) Lewis acid catalysis results in the formation of both the 1,4-cis and 1,4- trans isomers with the trans isomer being favoured and provides the possibility for the

1,2-trans isomer. The nucleophilic ring opening of 69, with primary, secondary, and tertiary alcohols, has been carried out in the presence of copper (II) and iron (III) Lewis acid catalysts to provide trans cyclopentenes 90 and 91 and cis cyclopentene 92 (Scheme

25).44(c)

Scheme 25. Lewis-acid catalyzed ring opening of bicyclic alkene 69 with primary, secondary, and tertiary alcohols.44(c)

Grignard and organozinc reagents provide additional means for the ring opening of heterobicyclic alkene 69. While allowing for the functionalization of cyclopentenes with alkyl groups, these copper (II) catalyzed reactions present the opportunity of forming the 1,2-cyclopentene as the major isomer.53, 54 This is unlike both the palladium and Lewis acid catalyzed reactions, each producing a 1,4 isomer as the major product.

The use of alkynyl, alkenyl, and aromatic Grignard reagents results in the formation of

1,2-trans 93, 1,4-trans 94, and trace 1,4-cis 95 while organozinc reagents allow for

33 asymmetric ring opening with the use of alkynyl nucleophiles and chiral phosphine ligands (Scheme 26).53, 54

Scheme 26. Copper (II) catalyzed nucleophilic ring opening using Grignard or Organozinc reagents.53, 54

According to studies recently reported by the Tam group, the C-O bond of bicycloheptene 69 can also be cleaved in reactions catalyzed by rhodium and ruthenium.

Unsymmetrical bicyclic alkene 97 undergoes a nucleophilic ring opening reaction with methanol, in the presence of the neutral ruthenium (II) catalyst Cp*RuCl(COD), to regio- and stereoselectivley produce 1,2-trans cyclopentene 98 (Scheme 27).46 Alternatively, exclusive formation of the 1,2-cis ring-opened product 99 takes place with the use of the cationic catalyst [CpRu(CH3CN)3]PF6 in methanol. The use of other alcohols with this cationic catalyst can result in the formation of both products with stereoselectivity of

70:30 to 100:0 in favour of 99.46

Rhodium(I)-catalyzed ring opening of compound 97 has also been achieved. In the presence of [RhCl(COD)]2, 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 underwent a

34 nucleophilic ring-opening reaction with various arylboronic acids to give 1,2-trans and

1,2-cis cyclopentene products in stereoselectivities (trans/cis) ranging from 50:50 to

100:0 (Scheme 28).47

Scheme 27. The nucleophilic ring opening of bicyclic alkene 97 with a cationic and neutral ruthenium catalyst.46

Scheme 28. Rhodium(I)-catalyzed ring opening of bicyclic alkene 97 with arylboronic acids.47

As previously stated, much attention has also been paid to the modification of the alkene component of 76. The oxidative cleavage of this carbon-carbon double bond is of use synthetically as it produces an easily functionalized diacid. Standard oxidizing conditions, commonly potassium permanganate under phase transfer conditions, are used to form a 1,4-cis ring opened product with a 5-membered pyrolidone framework.55

Though high yields can be obtained with this method, difficulties arise with selectivity and over-oxidation in the presence of sensitive functional groups. In recent years, a much milder method utilizing a ruthenium catalyst has been reported which allows for

oxidative cleavage in the presence of sensitive functional groups and allows improved

control over reaction products. This was evident when diastereomers of 102 were

cleaved in the presence of ruthenium (III) chloride to produce pyrolidone 103 with

limited epimerization of stereocentres (Scheme 29).56

Scheme 29. Oxidative cleavage of C=C bond using mild ruthenium (III) chloride catalyst conditions.56

The carbon-carbon double bond of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene can also

be cleaved by olefin metathesis reactions in order to achieve ring opening.57 This method

uses carbenes to cleave the unsaturation and subsequently form different olefins. Initial

implementation of olefin metathesis in the ring opening of heterobicycle 76 used Grubb’s

catalyst to produce 5-membered pyrolidone structures. An intramolecular ring-

opening/ring-closing metathesis reaction was later accomplished using Grubb’s second

generation catalyst and an external alkene (Scheme 30). Under these conditions 3-aza-2-

oxabicyclo[2.2.1]hept-5-ene 104 reacted to form isoxazolo[2,3a]pyridine-7-one 105 and

106 which arises from incorporation of the external alkene.57

Scheme 30. Metathesis reaction of bicyclic alkene 104 with Grubb’s 2nd generation catalyst.57

It may also be desirable to carry out the dihydroxylation of heterobicyclic alkene

76. For example, nucleoside analogues, such as 107, are cis-diols originating from a 3- aza-2-oxabicyclo[2.2.1]hept-5-ene with important biological properties as adenosine kinase inhibitors.34 Toward the total synthesis of these molecules, olefin 97 was di- hydroxylated in the presence of OsO4 and trimethylamine N-oxide to yield compound

108 (Scheme 31). The reaction was highly stereoselective and produced the exo-cis-diol only. This result has been attributed to the steric influence of the carbamate group which hinders attack of the osmium tetraoxide from the endo face.34

Scheme 31. Di-hydroxylation of heterobyciclic alkene 107 in the synthesis of synthetic nucleoside analogue 108.34

Alkylidene cyclopropanation is another transformation involving the carbon- carbon double bond of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene.51 As part of a study exploring secondary phosphine oxide complexes with platinum, heterobicyclic alkene

109 underwent a [2+1] cycloaddition with phenylethyne to produce benzylidenecyclopropane 110 in 75% yield (Scheme 32). The importance of this study not only lies in the novelty of carbon-carbon bond formation using platinum/SPO complexes, but also in the appeal of compound 110 as a synthetic precursor.51

Scheme 32. Alkylidene cyclopropanation heterobicyclic alkene 109 using a platinum/SPO complex.51

The olefin of strained bicyclic alkenes can also be functionalized through [3+2] cycloaddition reactions with azides to form triazolines.58 The reaction of heterobicyclic alkene 97 with benzyl azide produces a regioisomeric mixture of triazolines 111 and 112 in excellent yields (Scheme 33). The reaction was highly stereoselective, providing the exo triazolines only, however no regioselectivity was observed. Nonetheless, both regioisomers were able to undergo photochemical conversion to aziridine 113.58

Scheme 33. [3+2] cycloaddition of heterobicyclic alkene 97 and azides to form exo triazolines with subsequent conversion to aziridine.58

1.5. Scope of Thesis

It can be seen that the chemical transformations, including the ring opening chemistry and alkene modification, of the 3-aza-2-oxabicyclo[2.2.1]hept-5-enes have been studied extensively. In addition, many examples of [2+2] cycloadditions, together with those catalyzed by transition metals, are present in the literature. However, no investigations into the transition-metal catalyzed [2+2] cycloaddition of 3-aza-2- oxabicyclo[2.2.1]hept-5-enes has ever been made. Therefore, the aim of this project was to investigate the effects of the remote substituents on the ruthenium-catalyzed [2+2] cycloaddition of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 with unsymmetrical alkynes.

Once the [2+2] cycloaddition reactions were completed, it was envisioned that these cycloadducts could be used to access other functionalized bicyclic frameworks.

The ring opening of two cycloadducts was carried out as proof of concept.

Over the course of the investigation, a Ru-catalyzed [2+2] cycloaddion was carried out between 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 and (iodoethynyl)benzene.

This reaction yielded a complex mixture of products which contained not only the two regioisomeric cycloadducts, but also two regioisomers of another addition product. An effort to optimize the addition reaction between (iodoethynyl)benzene and a symmetrical bicyclic alkene is outlined. Further optimization and subsequent application to 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 is anticipated.

Chapter 2: Results and Discussion

2.1. Results and Discussion

In order to evaluate the regioselectivity of the [2+2] cycloaddition reaction it was first necessary to synthesize the heterobicyclic alkene as well as the unsymmetrical alkynes. Construction of the 3-aza-2-oxabicyclo[2.2.1]hept-5-enes can be achieved in high yields under oxidizing conditions (Scheme 34).33 Hydroxyl amine 114 is used to generate nitroso dienophile 115 which can then undergo a hetero-Diels-Alder reaction with cyclopentadiene 116 to produce the heterobicyclic cycloadduct 76.

Scheme 34. Synthesis of 3-aza-2-oxabicyclo[2.2.1]hept-5enes through a 33 hetero-Diels-Alder reaction.

A wide variety of unsymmetrical alkynes were also synthesized in order to explore various electronic and steric effects of this component. In general, the alkynes were synthesized by deprotonating the appropriate terminal acetylene and subsequently trapping the resulting anion with the desired electrophile (Scheme 35).

Scheme 35. General synthesis of the unsymmetrical alkynes.

For example, 4-methoxyphenyl acetylene can be deprotonated with nBuLi, followed by trapping with ethyl chloroformate to provide ethyl 4-

42 methoxyphenylpropynoate. This strategy was altered for certain alkynes that could not be synthesized by the previous method. For instance, the construction of the haloacetylene ethyl bromopropiolate required treatment of ethyl propiolate with N- bromosuccinimide and silver nitrate in acetone to yield the desired acetylene.

Once prepared, heterobicyclic alkene 97 was subjected to the different unsymmetrical alkynes in the presence of ruthenium catalyst Cp*Ru(COD)Cl in THF

(Table 2). Though all examples displayed modest regioselectivity of the two exo- cycloadducts, yields ranged from low to high. For the first set of alkynes one group was fixed as an ethyl ester (R2 = COOEt) while the other substituent was varied as different aromatic groups (R1 = Ar) (Table 2, entries 1-9). When this substituent was a methoxyphenyl group, 117a – 117c, the highest yield had the methoxy moiety in the meta position (Table 2, entry 2). A similar result was observed when the aromatic substituent possessed a chlorine group, 117d – 117e, with m-chlorophenyl displaying a higher yield than the corresponding para substituted group (Table 2, entries 4-5). Also following this trend are the tolyl substituents, 117f – 117g, with the m-methylbenzene group demonstrating a higher yield than the p-methylbenzene (Table 2, entries 6-7). Like previous aryl substituents, the trifluoromethylbenzene substituents 117h – 117i, showed higher yields with the trifluoromethyl group in the meta position (Table 2, entry 8).

When the R1 substituent is changed to an alkyl group, higher yields are observed with primary alkyl group 117j compared to secondary alkyl group 117k (Table 2, entries 10-

11). Modest yields are observed when R1 is a propagylic alcohol, 117l, or a TBS protected alcohol, 117m (Table 2, entries 12-13). Haloalkynes and alkynyl sulphides

117n – 117r result in yields that are moderate to low (Table 2, entries 14-18).

Table 2. Results of ruthenium-catalyzed [2+2] reactions with different unsymmetrical

alkynes.

Temp. Time Yield Ratio Entry Alkyne R1 R2 (oC) (d) (%)a (119:118)b

1 117a o-OMe-Ph COOEt 65 19 72 68:32

2 117b m-OMe-Ph COOEt 65 6 90 66:34

3 117c p-OMe-Ph COOEt 65 5 76 66:34

4 117d m-Cl-Ph COOEt 65 7 74 68:32

5 117e p-Cl-Ph COOEt 65 5 45 67:33

6 117f m-Me-Ph COOEt 65 7 85 66:34

7 117g p-Me-Ph COOEt 65 4 74 65:35

8 117h m-CF3-Ph COOEt 65 7 32 69:31

9 117i p-CF3-Ph COOEt 65 5 27 68:32

10 117j nBu COOEt 65 6 65 63:37

11 117k Cy COOEt 65 6 27 67:33

12 117l CMe2OH COOEt 65 6 47 73:27

13 117m CH2CH2OTBS COOEt 65 5 51 63:37

14 117n Br COOEt 65 5 51 59:41

15 117o Ph Br 65 7 25 57:43

16 117p Ph Cl 65 4 51 52:48

17 117q nBu S-Tol 65 5 18 76:24

18 117r Ph S-CH2CH3 65 6 24 59:41 a Isolated yields after column chromatography b Ratios based on 1H NMR

These ruthenium-catalyzed [2+2] cycloaddition could theoretically produce both exo and endo cycloadducts, however, based on the results of previous Tam group studies,

1 only exo products were expected. Using the coupling constant of Hb in the H NMR it was possible to verify the exo isomerism of the cycloadducts (Figure 10). Computational studies show that the dihedral angle between protons Ha and Hb in an exo addition product such as 120a is in the range of 70-75o.31 The Karplus curve indicates that this corresponds to a very small coupling constant (J~0-2 Hz). Alternatively, an endo cycloadduct like 120b would have a dihedral angle on the scale of 35-40o resulting in a coupling constant of 6-9 Hz.31 The cycloadducts synthesized over the course of this investigation did not display any noticeable coupling between Ha and Hb, confirming the presence of exo cycloadducts.

Figure 10. Exo versus endo cycloadducts.31

Though each [2+2] reaction carried out during this study produced two exo- regiosiomers, only a few examples had cycloadducts that were separable by column chromatography. Once these regioisomers, such as 118c and 119c, were physically separated, NMR techniques including HSQC and COSY were used to identify each proton and carbon (Figure 11 and Figure 12).

h j i d a g b c e e

Figure 11. 1H NMR of cycloadduct 118c.

O,L,P,M N, Q R E

A H D C B K

I J

Figure 12. 13C NMR of cycloadduct 118c.

Following the elucidation of the proton and carbon spectra it was possible to distinguish the major and minor regioisomers using a gradient NOESY experiment.

Though many of the protons are close enough in space give an NOE, it is the appearance of a few key peaks on the spectrum that will differentiate one regioisomer from the other.

In the structure proposed for regioisomer 118c, HJ would display an NOE with Hb and not Hc while Hf would show an NOE with Ha and not Hd (Figure 13).

Figure 13. Using gradient NOESY experiments to distinguish the regioisomers.

In order to provide conclusive evidence, it is also necessary to demonstrate that compound 119c is the opposite regioisomer. According to its structure, HJ would show an NOE with Hc and not Hb, and Hf would display an NOE with Hd and not Ha. Once the experiment was carried out, the gradient NOESY spectrum of regioisomer 118c exhibited a peak demonstrating the NOE between Ha and Hf (Figure 14).

Another region of the same spectrum revealed the NOE between Hb and aromatic proton HJ (Figure 15). The COSY spectrum has already confirmed that Ha and Hb are 3 bonds away, attached to adjacent carbon atoms (Figure 16). Therefore, it was concluded that the aromatic substituent and the BOC group of the minor regioisomer, 118c, were on

47 the same side of the bicyclic structure. A similar gradient NOESY experiment allowed the opposite regiochemistry to be assigned to the major product, 119c.

a - f

Figure 14. NOESY experiment showing an NOE between Ha and Hf of 118c.

b - j

Figure 15. NOESY experiment showing an NOE between Hb and Hj of 118c.

d –c a –b

Figure 16. The COSY spectrum of compound 118c which demonstrates that

Ha and Hb as well as Hc and Hd are on adjacent carbons.

Once a [2+2] cycloadduct has been constructed and distinguished from its regioisomer, the product can then be used to synthesize more complex molecules. Ring- opening of [2+2] cycloadducts to a [3.2.0] bicyclic structure is one way that these products can be used to access more complex molecular structures. Several natural products have been identified which contain a [3.2.0] heptane skeleton (Figure 17).

Figure 17. Natural products containing a [3.2.0] heptane skeleton.59

PC-M4, 121, was isolated from the fungus Penicillium crustosum and may be a biosynthetic precursor to the penitrems.59 Also, Avicennamine 122, isolated from the shrub, Zanthoxylum avicennae acts as a platelet aggregation inhibitor, a DNA isomerise inhibitor, and has antibacterial and cyctotoxic properties.60

One of the many transformations previously carried out on the 3-aza-2-oxabicyclo[2.2.1]hept-5-ene precursor was a reductive cleavage of the relatively weak N-O bond to form a cyclopentene ring-opened product. A similar reductive cleavage reaction has been applied to selected [2+2] cycloadducts resulting in the formation of highly functionalized [3.2.0] bicyclic ring systems (Scheme 36).

Scheme 36. Ring-opening of the [2+2] cycloadducts through reductive cleavage of the N-O bond.

Addition products 119c and 119l were subjected to molybdenumhexacarbonyl in the presence of an acetonitrile/water mixture providing ring opened products 123 and 124

50 respectively. Cycloadduct 119c provided the corresponding [3.2.0] bicycloheptene in a higher yield of 90% compared to cycloadduct 119l with a yield of 71%.

Some challenges were encountered when attempting to characterize these ring opened products through standard one-dimensional NMR techniques. Several of the expected peaks appeared to be missing from the 13C NMR despite a promising 1H NMR spectrum. This was found to be due to a so-called intermediate chemical exchange which leads to near coalescence of several 13C lines in the spectrum.61 For example, the 13C

NMR spectrum of the ring-opened product 123 is missing five peaks (Figure 18).

Figure 18. Five carbons of compound 123 are virtually undetectable by 1D 13C NMR.

Though these peaks are nearly invisible in a one dimensional experiment, they show up clearly in a two-dimensional correlation spectrum. For example, the HSQC

NMR spectrum of 123 shows a correlation between the He protons and a carbon unseen on the left-hand, one-dimensional, 13C projection (Figure 19). These two-dimensional experiments involve detection of the protons, whose coupling remains largely unaffected.

As a result, the 2D NMR techniques HSQC and HMBC were necessary to fully characterize and clearly identify the ring opened products.

Figure 19. A carbon unseen on the 1D projection is detected in an HSQC of compound 123.

2.2. Significance and Application

As previously discussed, there are no reports of ruthenium-catalyzed [2+2] cycloadditions on these 3-aza-2-oxabicyclo[2.2.1]hept-5-ene substrates and the regioselectivity of these reactions has not been previously investigated. These investigations into the preferential formation of one regioisomer over the other have provided some insight into the electronics of these heterobicycles and how they compare to their carbocyclic analogues. In the ruthenium-catalyzed [2+2] reactions of 2- substituted norbornenes, the oxidative addition transition state was seen, in the previous chapter, to control the regioselectivity. Electrostatic interactions between the alkene and the alkyne components resulted in energy differences between the possible transition states causing the formation of a major and a minor regioisomer. The favourable transition state for the 2-substituted norbornenes is stabilized by a favourable electrostatic interaction between the alkyne carbon and the alkene carbon with which it is forming a bond.31

As the same mechanism is likely in operation, this theory can be extended to the reactions with the heterobicyclic alkenes. Like the alkynes used in the norbornene study, an alkyne such as 117c will have a Cb that is more negative than Ca due to the electron- withdrawing properties of the COOEt substituent (Scheme 37). It can also be hypothesized that the most favourable transition state will form a C5 – Cb bond in which

C5 is slightly positive and Cb is slightly negative, creating the stabilizing electrostatic interaction. This may cause a transition state such as 125 to be slightly favoured leading to the major regioisomer 119c, with the ethyl ester syn to the BOC group. It is also possible that the bulky carbamate offers steric hindrance to the ruthenium if it were to

53 add adjacent to C5. In actual fact, the mild regioselectivity observed in these reactions may be due to a combination of electronic and steric effects.

δ- δ+ δ+ δ-

Scheme 37. Possible electrostatic interactions in the transition state leading to the major regioisomeric product.

As well as contributing to the general knowledge of 3-aza-2- oxabicyclo[2.2.1]hept-5-ene, the [2+2] cycloadducts produced could be employed in the synthesis of more complex molecules. This project has demonstrated that the [2+2] cycloadduct of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 and an alkyne can also be used to create a functionalized [3.2.0] bicyclic structure and a few natural products were shown to contain a [3.2.0] heptene core.

Additional molecular frameworks have been synthesized from the cycloadducts of other bicyclic alkynes. Further studies could explore the feasibility of analogous treatment of the 3-aza-2-oxabicyclo[2.2.1]hept-5-ene cycloadducts. For example, cyclooctane derivatives are found in a variety of natural products yet the formation of these medium-sized rings can be difficult to achieve. A nickel-catalyzed [2+2] cycloaddition followed by expansion of the resulting cyclobutene ring was reported by

Cheng and co-workers as an effective route to functionalized 8-membered rings (Scheme

38).62 A similar ring expansion of the cycloadducts synthesized during the course of this project may be envisioned to produce an 8-membered heterocycle.

Scheme 38. Ring expansion of a cyclobutene to produce an 8-membered ring.62

An additional way that [2+2] cycloadducts can be used to form more complex structures is the derivatization of the double bond present in the cyclobutene ring.63 Two new quaternary centres were formed in the highly stereoselective Simmons-Smith cyclopropanation of compound 126 (Scheme 39).

Scheme 39. Simmons-Smith cyclopropanation of a [2+2] cycloadduct and possible cleavage sites.63

The resulting cis-anti-cis adduct 127 could then be cleaved along bonds a, b, or c to synthesize additional frameworks.63 Similar treatment of the cycloadducts of 3-aza-2- oxobicyclo[2.2.1]hept-5-enes may be desirable as a means of synthesizing more complex heterocyclic systems (Scheme 40).

Scheme 40. Potential treatment of the cycloadducts of 3-aza-2-oxobicyclo[2.2.1]hept-5-ene 97.

2.3. Conclusions

In summary, the first examples of ruthenium-catalyzed [2+2] cycloaddition reactions of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with unsymmetrical alkynes have been demonstrated. Reactions in the presence of Cp*Ru(COD)Cl in THF were found to give two regioisomers of the exo-addition product. Low to appreciable yields of the cycloadducts were observed with modest regioselectivies. Ring opening of the addition products to a functionalized [3.2.0] heptene provides the opportunity to access more complex structures from relatively simple precursors.

Chapter 3: Optimization of a Haloalkynylation Reaction

3.1. Introduction

Over the course of our investigation into Ru-catalyzed [2+2] cycloadditions of 3- aza-2-oxabicyclo[2.2.1]hept-5-ene 97, a reaction was carried out between heterobicyclic alkene 97 and 1-iodo-2-phenylethyne 117s (Scheme 41). A complex mixture of products was produced which was thought to include the regioisomeric [2+2] cycloadducts, 118s and 119s, as well as two regioisomeric addition products, 129 and 130.

Scheme 41. Reaction with alkyne 117 appears to produce addition products alongside [2+2] cycloadducts.

This was reminiscent of a previous Tam group study on the ruthenium-catalyzed

[2+2] cycloaddition of norbornadiene. The investigation focused on alkynyl halides as a means of exploring the scope and limitations of Ru-catalyzed [2+2] cycloadditions.64 As reactions with non-electron-deficient and bulky alkynes gave predictably low yields, it was anticipated that reactions involving alkynyl halides, with their innate electron- withdrawing properties, would possess enhanced rates. In addition, a cycloadduct with a halide moiety could be further engaged in various coupling reactions to obtain compounds which are not easily prepared via a direct cycloaddition.

It was found that alkynyl halides were generally compatible with the Ru-catalyzed

[2+2] cycloaddition reaction.64 When norbornadiene was reacted with various alkynyl halides in the presence of Cp*Ru(COD)Cl, the appropriate cycloadducts were obtained in moderate to good yields (Scheme 42). However, an interesting result was encountered upon investigation of the phenyl series of alkynyl substrates (R=Ph). Though the alkynyl chloride and bromide reactions proceeded efficiently, 1-iodo-2-phenylethyne provided an addition product 131 in 26% yield together with the usual [2+2] addition product 132

(41% yield) (Figure 20).64

Scheme 42. Ru-catalyzed [2+2] cycloadditions of norbornadiene and various alkynyl halides.64

Figure 20. Products of the Ru-catalyzed [2+2] cycloadditions of norbornadiene and 1-iodo-2-phenylethyne.64

Two characteristics of 1-iodo-2-phenylethyne were used to rationalize the formation of by-product 131. Firstly, iodine is less electronegative than either chlorine or bromine and, as the reaction proceeds faster for strong electron-withdrawing groups, the rate of reaction is decreased.64 Secondly, the carbon-iodide bond is relatively weak

59 compared to the bond between carbon and chlorine or carbon and bromine. Therefore, the oxidative insertion of ruthenium into the carbon-iodide is much easier. It is a combination of these two factors that result in haloalkynylation in the case of 1-iodo-2- phenylethyne and not 1-bromo-2-phenylethyne or 1-chloro-2-phenylethyne. This reaction is thought to be the first reported case of ruthenium catalyzing the haloalkynylation of an alkynyl halide across a carbon-carbon double bond.64

When this ruthenium-catalyzed haloalkynylation reaction resurfaced in the Ru- catalyzed [2+2] cycloaddition study with 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97, it was envisaged that the reaction could be optimized in favour of the haloalkynylation product.

As the products of reactions with symmetrical substrates are far easier to characterize, an optimization study undertaken using norbornadiene and 1-iodo-2-phenylethyne.

3.2. Results and Discussion

Before various aspects of the haloalkynylation reaction could be explored, it was necessary to synthesize the alkyne starting material. The terminal phenylacetylene was submitted to N-iodosuccinimide in the presence of silver nitrate to produce the required

1-iodo-2-phenylethyne (Scheme 43).64

Scheme 43. Synthesis of 1-iodo-2-phenylethyne from phenylacetylene.

As the desired addition product was originally observed by the Tam group when norbornadiene and 1-iodo-2-phenylethyne were submitted to Cp*Ru(COD)Cl in THF for

72 h at a temperature of 65 oC, this reaction was carried out first as a control. In order to facilitate the optimization process, quantitative NMR studies were used to detect the presence of both the [2+2] cycloadduct and the haloalkynylation product in the crude reaction. Following removal of the ruthenium catalyst by filtration, a known amount of toluene or dichloroethane were added to the crude reaction mixture. Peak integration of the 1H NMR was then used to determine the yield.

Efforts to optimise the addition reaction were initiated with the screening of various ruthenium catalysts (Table 3). Use of a cationic ruthenium catalyst yielded none of the addition product with sole production of the [2+2] cycloadduct (Table 3, entries 2-

3). It was envisioned that the presence of an iodide ligand on the ruthenium catalyst would favour the addition reaction, however, use of the CpRu(COD)I catalyst did not result in the formation of any of the haloalkynylation product (Table 3, entry 4). It is interesting to note that this catalyst produced a higher yield of the [2+2] cycloadduct than the original ruthenium catalyst. The Ru(COD)Cl2 catalyst again produced no observable addition products with a very low yield of the cycloaddition product (Table 3, entry 5). A number of other ruthenium catalysts, possessing a variety of ligands, were also employed; however, these catalysts produced neither the desired addition product nor the [2+2] cycloadduct (Table 3, entries 6-12). Therefore, among the catalysts tested,

Cp*Ru(COD)Cl was found to produce the highest yield of addition product 131.

Table 3. Catalyst optimization for Ru-catalyzed haloalkynylation between 23 and 117s.

Entry Catalyst Yield 132 (%)a Yield 131 (%)a 1 Cp*Ru(COD)Cl 32 - 33 18 - 24

2 [CpRu(CH3CN)]PF6 25 - 34 0

3 [Cp*Ru(CH3CN)]PF6 25 0 4 CpRu(COD)I 54 0

5 Ru(COD)Cl2 4 0

6 0 0

7 CpRuCl(COD) 0 0 8 Ind*Ru(COD)Cl 0 0

9 Ru(C5H5)Cl(P(C5H5)2 0 0

10 RuCl(CO)2(C32H28N) 0 0

11 [RuCl2(p-cymene)]2 0 0

12 RuCl2(PPh3)3 0 0 a Yields obtained by 1H NMR using toluene and DCE internal standards

Proceeding with Cp*Ru(COD)Cl as the optimal catalyst, efforts were made to attain the most favourable solvent (Table 4). Though solvents with varying properties were screened, no new solvent was found in which the reaction was successful.

Table 4. Attempts to optimize the solvent system for the Ru-catalyzed haloalkynylation between 23 and 117s.

Solvent Yield A Yield B Acetone Methanol No Products Detected DMF 1,4-dioxane

Clearly, further investigations are necessary to make this reaction a feasible method for the production of addition product 131. Once optimized for the symmetrical norbornadiene substrate it can be applied to other bicyclic alkenes. Furthermore, a study on regioselectivity of the haloalkynylation of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 could potentially be undertaken.

3.3. Recent Developments in the Field

Unknown at the time of our investigation, researchers have recently reported the palladium-catalyzed reaction of haloalkynes with norbornene derivatives.65 They first reacted phenylethynyl bromide with norbornene and a catalytic amount of Pd(OAc)2, expecting to obtain addition product 133 (Scheme 44). Surprisingly, this compound was not observed and instead they acquired 2-bromo-7-(2-

63 phenylethynyl)bicyclo[2.2.1]heptane product 134. This is thought to be the first reported example of the direct formation of a 7-alkynyl bromonorbornane.65

Scheme 44. The palladium-catalyzed bromoalkynylation of norbornene.65

The scope of this reaction was studied extensively and this mode of C7 functionalization was found to be applicable to a number of norbornene derivatives as well as a wide variety of haloalkynes.65 Norbornene underwent sucessful palladium- catalyzed bromoalkynylation with both electron-rich and electron-poor phenylethynyl bromides to selectively produce the appropriate alkynylation products in high yields

(Scheme 45). Like the phenylethynyl bromides, reaction with 1-iodo-2-phenylethyne yielded a 7-alkynyl iodonorbornane in excellent yields.65 These products contrast with those observed in the previously discussed ruthenium-catalyzed study by the Tam group using similar substrates.64

Equally surprising was the application of the optimized palladium conditions to the less strained cyclic system of cyclooctene.65 Though researchers anticipated the formation of a 2-propynyl bromide derivative, a [2+2] cycloadduct was obtained in its place (Scheme 46). This [2+2] cycloaddition also takes place when the phenylethynyl

64 bromide is substituted for 1-iodo-2-phenylethyne. This proves to be an interesting result as the cycloaddition of monocyclic alkenes and alkynes is generally difficult to achieve.65

Scheme 45. Palladium-catalyzed haloalkynylation of norbornene with various alkynyl

halides.65

Scheme 46. Palladium-catalyzed reaction of phenylethynyl bromide with cyclootene.65

3.4. Conclusions

In summary, with the ruthenium-catalyst Cp*Ru(COD)Cl phenylethynyl bromide

117o cleanly undergoes a [2+2] cycloaddition with a bicyclic alkene to provide the corresponding cycloadduct. 1-iodo-2-phenylethyne, however, provides a mixture of the

[2+2] cycloadduct and the 1,2-addition product under the same conditions.64 Efforts to optimize this ruthenium-catalyzed reaction in favour of the 1, 2-addition product were unsuccessful.

On the other hand, using the palladium-catalyst Pd(OAc)2 both phenylethynyl bromide 117o and 1-iodo-2-phenylethyne 117s produce 7-alkynyl halonorbornanes.

Meanwhile similar palladium-catalyzed conditions with cyclooctene provide synthesis of a [2+2] cycloadduct.65 Evidently, a haloalkyne has the opportunity to react in several different ways when faced with different transition metal catalysts or alkene structures.

Chapter 4: Experimental

4. Experimental

General Information: All reactions were carried out in an atmosphere of dry nitrogen at ambient temperature unless otherwise stated. Column chromatography was performed on

230-400 mesh silica gel (obtained from Silicycle) using flash column chromatography techniques.66 Analytical thin-layer chromatography (TLC) was performed on Silicycle precoated silica gel F254 plates. All glassware was oven dried. Infrared spectra were taken on a Thermo Scientific Nicolet 380 FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on Bruker Avance-400 and 600 spectrometers. Chemical shifts for 1H

NMR spectra are reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (chloroform:  7.26 ppm). Chemical shifts for

13C NMR spectra are reported in parts per million (ppm) from tetramethylsilane with the solvent as the internal standard (deuterochloroform:  77.0 ppm). High resolution mass spectra were done by Mass Spectrometry at Queen’s University, Kingston, Ontario.

Reagents: Unless stated otherwise, commercial reagents were used without purification.

Solvents were purified by distillation under dry nitrogen: from CaH2 (1,2-dichloroethane, hexanes) and from potassium/benzophenone (THF). Cp*Ru(COD)Cl was bought from

Strem Chemicals. Norbornadiene was purchased from Sigma-Aldrich. Alkynes 117a –

117i were prepared according to the following procedure and NMR spectra obtained matched those found in the literature.67,68,69 Alkynes 117j – 117l and 117m – 117s were prepared according to literature procedures.70,71,64 Alkyne 117n was synthesized using previously published methods.72 Alkene 97 was prepared according to previously described procedures.33

General procedure for ruthenium-catalyzed [2+2] cycloaddition reactions of

3-Aza-2-oxabicyclo[2.2.1]hept-5-enes with unsymmetrical alkynes. 3-Aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (0.2-1.7 mmol, 1 equiv.) and an unsymmetrical alkyne (1 equiv.) were added to seperate oven-dried vials. These vials were purged with nitrogen and transferred into a dry box. In the dry box, to a third oven-dried vial was added

Cp*Ru(COD)Cl (3 mol%). THF was added to the vial containing the bicyclic alkene and this was transferred slowly to the vial containing the ruthenium catalyst. Likewise, THF was added to the vial containing the alkyne and this was transferred to the vial containing the Ru-catalyst and bicyclic alkene. The vial was then sealed with a screw cap and removed from the dry box and heated to 65 oC. The crude products were purified by column chromatography (EtOAc – hexanes mixture) and concentrated in vacuo to give the corresponding [2+2] cycloadduct.

Cycloadducts 118a and 119a. Following the above procedure with ethyl 2- methoxyphenylpropynoate 117a (201.1 mg, 1.02 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (209.0 mg, 1.02 mmol), the reaction was allowed to stir at 65 oC for 456 hours. The crude product was purified by column chromatography

(gradient of 0-30% EtOAc in hexanes) to provide cycloadducts 118a (94.7 mg, 0.236 mmol, 23%) and 119a (201.2 mg, 0.501 mmol, 49%).

118a: Rf 0.38 (EtOAc:hexanes = 30:70); IR (neat, NaCl)

2978 (m), 1736 (m), 1704 (s), 1596 (m), 1466 (m) cm-1; 1H

NMR (CDCl3, 400 MHz): δ 8.33 (m, 1H), 7.32 (m, 1H), 6.94

(t, 1H, J = 7.4 Hz), 6.87 (d, 1H, J = 8.4 Hz), 4.76 (m, 1H), 4.61 (br s, 1H), 4.17 (q, 2H, J

= 7.1 Hz), 3.86 (s, 3H), 3.47 (m, 1H), 3.23 (m, 1H), 2.22 (d, 1H, J = 11.2 Hz), 1.68 (d,

13 1H, J = 11.4 Hz), 1.50 (s, 9H), 1.27 (t, 3H, J = 7.1 Hz); C NMR (APT, CDCl3, 100

MHz): δ 162.3, 158.3, 157.1, 154.1, 132.0, 131.8, 129.8, 120.8, 120.4, 110.8, 81.8, 77.7,

+ 60.3, 58.3, 55.1, 47.0, 45.6, 30.7, 28.2, 14.2. HREI calcd. for C22H27NO6 (M ): m/z

401.1838; found: m/z 410.1849.

119a: Rf 0.32 (EtOAc:hexanes = 30:70); IR (neat, NaCl)

2978 (m), 1704 (s), 1596 (m), 1466 (m) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 8.35 (m, 1H), 7.32 (m, 1H), 6.94 (m,

1H), 6.85 (d, 1H, J = 8.3 Hz), 4.61 (m,1H), 4.20 (q, 2H, J = 7.2 Hz), 3.81 (s, 3H), 3.48

(m, 1H), 3.23 (m, 1H), 2.23 (d, 1H, J = 11.5 Hz), 1.64 (br d, 1H, J = 10.5 Hz), 1.50 (s,

13 9H), 1.29 (t, 3H, J = 7.1 Hz); C NMR (APT, CDCl3, 100 MHz): δ 162.3, 158.3, 157.6,

154.7, 132.0, 131.9, 129.5, 120.7, 120.4, 110.8, 82.0, 78.0, 60.3, 58.1, 55.1, 48.5, 44.3,

+ 30.6, 28.2, 14.2. HREI calcd. for C22H27NO6 (M ): m/z 401.1838; found: m/z 401.1851.

Cycloadducts 118b

and 119b. Following

the above procedure

with ethyl 3- methoxyphenylpropiolate 117b (106.8 mg, 0.542 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (110.5 mg, 0.541 mmol), the reaction was allowed to stir at 65oC for 144 hours. The crude product was purified by column chromatography

(gradient of 20-30% EtOAc in hexanes) to provide an inseparable mixture (66:34) of cycloadducts (195.1 mg, 0.486 mmol, 90%). Rf 0.23 (EtOAc:hexanes = 20:80); IR (neat,

NaCl) 2923 (s), 2853 (s), 1709(m), 1599 (w), 1460 (s), 1376 (s), 1043 (w) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 7.71 (m, 1H), 7.36-7.20 (m, 2H), 6.86 (m, 1H), 4.72 (m, 1H), 4.57

(s, 0.66H), 5.53 (s, 0.33H), 3.76-3.75 (m, 3H), 3.30 (m, 1H), 3.20 (m, 1H), 2.08 (m, 1H),

13 1.65 (m, 1H), 1.45-1.44 (m, 9H), 1.29-1.23 (m, 3H); C NMR (APT, CDCl3, 100 MHz):

δ 161.9, 161.8, 159.6, 159.5, 157.2, 157.1, 155.9, 155.4, 132.8, 132.7, 129.4, 129.1,

128.8, 120.8, 117.4, 113.3, 82.1,82.0, 77.2, 76.7, 60.3, 57.6, 57.3, 55.1, 44.8, 44.0, 43.1,

+ 42.7, 30.7, 28.0, 14.1. HRESI calcd. for C22H27NO6 (M ): m/z 401.1838; found: m/z

401.1845.

Cycoadducts 118c and 119c. Following the above procedure with ethyl 4- methoxyphenylpropynoate 117c (335.4 mg, 1.63 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (326.6 mg, 1.66 mmol), the reaction was allowed to stir at 65 oC for 120 hours. The crude product was purified by column chromatography (30%

EtOAc in hexanes) to provide cycloadducts 118c (170.2 mg, 0.424 mmol, 26%) and 119c

(325.7 mg, 0.811 mmol, 50%). Relative regio- and stereochemistry of each isomer was confirmed by various 2D NMR (COSY, HSQC, HMBC) experiments and a gradient

NOESY experiment preformed on a 400 MHz NMR spectrometer.

Cycloadduct 118c: Rf 0.38 (EtOAc:hexanes = 30:70); IR

(neat, NaCl) 2977 (m), 1736 (m), 1701 (s), 1603 (s), 1509

-1 1 (s) cm ; H NMR (CDCl3, 400 MHz): δ 7.99-7.95 (m,

2H), 6.90-6.87 (m, 2H), 4.76-4.75 (m, 1H), 4.23-4.15 (m, 2H), 3.81 (s, 3H), 3.34 (m, 1H),

3.23 (m, 1H), 2.13 (d, 1H, J = 11.4 Hz), 1.69 (d, 1H, J = 11.4 Hz), 1.50 (s, 9H), 1.29 (t,

13 3H, J = 7.1 Hz); C NMR (APT, CDCl3, 100 MHz): δ 162.2, 161.6, 157.2, 155.3, 130.7,

125.9, 124.7, 113.9, 82.2, 77.5, 60.2, 57.3, 55.3, 43.8, 42.9, 30.8, 28.1, 14.2. HREI calcd.

+ for C22H27NO6 (M ): m/z 401.1838; found: m/z 401.1823.

Cycloadduct 119c: Rf 0.29 (EtOAc:hexanes = 30:70);

IR (neat, NaCl) 2978 (m), 1737 (m), 1703 (s), 1603 (s),

-1 1 1509 (s) cm ; H NMR (CDCl3, 400 MHz): δ 7.91 (d,

2H, J = 8.8 Hz), 6.86 (d, 2H, J = 8.9 Hz), 4.73 (m, 1H), 4.59 (s, 1H) 4.22-4.17 (m, 2H),

3.78 (s, 3H), 3.29 (m, 1H), 3.22 (m, 1H), 2.11 (d, 1H, J = 11.4 Hz), 1.65 (d, 1H, J = 11.8

13 Hz), 1.47 (s, 9H), 1,29 (t, 1H, J = 7.2 Hz); C NMR (APT, CDCl3, 100 MHz): δ 162.3,

161.6, 157.3, 155.8, 130.7, 125.5, 124.7, 113.9, 82.0, 76.8, 60.1, 57.9, 55.2, 44.6, 42.5,

+ 30.8, 28.1, 14.2. HREI calcd. for C22H27NO6 (M ): m/z 401.1838; found: m/z 401.1847.

Cycloadducts 118d

and 119d. Following

the above procedure

with ethyl 3- chlorophenylpropiolate 117d (42.0 mg, 0.206 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-

5-ene 97 (41.1 mg, 0.209 mmol), the reaction was allowed to stir at 65oC for 168 hours.

The crude product was purified by column chromatography (gradient of 15-40% EtOAc in hexanes) to provide an inseparable mixture (68:32) of cycloadducts (60.1 mg, 0.148 mmol, 74%). Rf 0.32 (EtOAc:hexanes = 30:70); IR (neat, NaCl) 2979 (m), 1736 (m),

-1 1 1705(s) cm ; H NMR (CDCl3, 400 MHz): δ 8.04 (m, 1H), 7.81 (d, 0.3H, J = 7.2 Hz),

7.74 (d, 0.7H, J = 7.2 Hz), 7.37-7.30 (m, 2H), 4.78 (m, 1H), 4.63 (s, 0.68H), 4.59 (s,

0.32H), 4.28-4.21 (m, 2H), 3.36 (m, 1H), 3.28 (m, 1H), 2.10 (m, 1H), 1.72 (m, 1H), 1.51-

13 1.50 (m, 9H), 1.36-1.30 (m, 3H); C NMR (APT, CDCl3, 100 MHz): δ 161.9, 161.8,

157.4, 157.3, 154.3, 153.7, 134.7, 133.2, 130.8, 130.7, 130.4, 129.9, 129.8, 128.8, 128.7,

126.7, 82.5, 82.4, 77.2, 76.6, 60.7, 57.6, 57.2, 44.9, 44.3, 43.2, 43.0, 30.8, 28.2, 14.2.

35 + HRESI calcd. for C21H24 ClNO5 (M+H) : m/z 406.1421; found: m/z 406.1420.

Cycloadducts 118e

and 119e.

Following the above procedure with ethyl 4-chlorophenylpropynoate 117e (40.3 mg, 0.19 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (40.5 mg, 0.21 mmol), the reaction was allowed to stir at

65oC for 120 hours. The crude product was purified by column chromatography (20%

EtOAc in hexanes) to provide an inseparable mixture (67:33) of cycloadducts (38.0 mg,

0.0936 mmol, 45%). Rf 0.30 (EtOAc:hexanes = 20:80); IR (neat, NaCl) 2979 (s), 2934

-1 1 (w), 1736 (m), 1706 (s), 1488 (m) cm ; H NMR (CDCl3, 400 MHz): δ 7.94 (d, 0.7H, J =

8.5 Hz), 7.90-7.89 (m, 1.3H), 7.37-7.35 (m, 2H), 4.78 (s, 0.33H), 4.76 (s, 0.67H), 4.63 (s,

0.67H), 4.57 (s, 0.33H), 4.28-4.18 (m, 2H), 3.36 (m, 1H), 3.27 (m, 1H), 2.11 (m, 1H),

13 1.72 (m, 1H), 1.51-1.50 (m, 9H), 1.34-1.29 (m, 3H); C NMR (APT, CDCl3, 100 MHz):

δ 162.1, 162.0, 157.4, 157.3, 154.8, 154.3, 137.0, 136.9, 130.2, 130.1, 130.0, 129.6,

129.3, 129.0, 82.5, 82.4, 77.3, 76.7, 60.7, 57.7, 57.2, 44.8, 44.3, 43.2, 43.0, 30.9, 28.2,

35 + 14.3. HRESI calcd. for C21H24 ClNO5 (M+H) : m/z 406.1421; found: m/z 406.1432.

Cycloadducts 118f

and 119f. Following

the above procedure

with ethyl 3- tolylpropiolate 117f (191.0 mg, 1.01 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97

(202.0 mg, 1.03 mmol), the reaction was allowed to stir at 65oC for 120 hours. The crude

73 product was purified by column chromatography (20% EtOAc in hexanes) to provide an inseparable mixture (66:34) of cycloadducts (336.2 mg, 0.873 mmol, 85%). Rf 0.28

(EtOAc:hexanes = 20:80); IR (neat, NaCl) 2979 (m), 1739 (m), 1705 (s) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 7.76-7.74 (m, 1.34H), 7.67 (d, 0.66H, J=7.6), 7.22 (m, 1H), 7.15

(m, 1H), 4.73 (m, 1H), 4.58 (s, 0.66H), 4.55 (0.34H), 4.23-4.13 (m, 2H), 3.32 (m, 1H),

3.21 (m, 1H), 2.31 (s, 3H), 2.08 (m, 1H), 1.65 (m, 1H), 1.46-1.45 (m, 9H), 1.30-1.24 (m,

13 3H); C NMR (APT, CDCl3, 100 MHz): δ 162.1, 162.0, 157.3, 157.2, 156.1, 155.6,

138.2, 131.7, 131.6, 129.2, 128.7, 128.5, 128.4, 125.9, 82.2, 82.1, 77.4, 76.8, 60.4, 57.7,

+ 57.3, 44.8, 44.0, 43.1, 42.7, 30.8, 28.1, 21.3, 14.2. HRESI calcd. for C22H27NO5 (M ): m/z 385.1889; found: m/z 385.1898.

Cycloadducts 118g

and 119g.

Following the above procedure with ethyl 4-tolylpropiolate 117g (191.3 mg, 1.02 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (201.9 mg, 1.02 mmol), the reaction was allowed to stir at 65oC for 96 hours. The crude product was purified by column chromatography

(gradient of 0-30% EtOAc in hexanes) to provide an inseparable mixture (65:35) of cycloadducts (283.2 mg, 0.735 mmol, 74%). Rf 0.29 (EtOAc:hexanes = 20:80); IR (neat,

-1 1 NaCl) 2979 (s), 1740 (s), 1704 (s) cm ; H NMR (CDCl3, 400 MHz): δ 7.89-7.83 (m,

2H), 7.20-7.17 (m, 2H), 7.46 (m, 1H), 4.61 (s, 0.65H), 4.57 (s, 0.35H), 4.25-4.19 (m,

2H), 3.35 (m, 1H), 3.24 (m, 1H), 2.35-2.34 (m, 3H), 2.12 (m, 1H), 1.68 (m, 1H), 1.50-

13 1.49 (m, 9H), 1.33-1.28 (m, 3H); C NMR (APT, CDCl3, 100 MHz): δ 162.2, 162.1,

157.3, 157.2, 156.1, 155.5, 141.4, 129.3, 129.0, 128.8, 128.7, 127.7, 127.4, 82.2, 82.1,

77.4, 76.8, 60.3, 57.8, 57.3, 44.7, 43.9, 43.0, 42.7, 30.8, 28.1, 21.5, 14.2. HRESI calcd.

+ for C22H27NO5Na (M+Na) : m/z 408.1787; found: m/z 408.1776.

Cycloadducts 118h

and 119h. Following

the above procedure

with ethyl 3- trifluoromethylphenylpropiolate 117h (64.2 mg, 0.265 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (52.0 mg, 0.264 mmol), the reaction was allowed to stir at 65oC for 165 hours. The crude product was purified by column chromatography (30%

EtOAc in hexanes) to provide an inseparable mixture (69:31) of cycloadducts (29.4 mg,

0.841 mmol, 32%). Rf 0.44 (EtOAc:hexanes = 30:70); IR (neat, NaCl) 2980 (m), 2933

(w), 1736 (m), 1708 (s), 1621 (w), 1335 (s), 1306 (s), 1166 (s), 1129 (s) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 8.33 (m, 1H), 8.10 (d, 0.31H, J = 7.6 Hz), 8.03 (d, 0.69H, J = 7.8

Hz), 7.64 (m, 1H), 7.53 (m, 1H), 4.81 (m, 1H), 4.66 (s, 0.69H), 4.61 (s, 0.31H), 4.30-4.23

(m, 2H), 3.42 (m, 1H), 3.32 (m, 1H), 2.13 (m, 1H), 1.52-1.51 (m, 9H), 1.36-1.31 (m, 3H);

13 C NMR (APT, CDCl3, 100 MHz): δ 161.9, 161.8, 157.4, 157.2, 154.0, 153.4, 132.2,

131.7, 131.6, 131.4, 131.2, 131.1, 130.9, 129.3, 127.2 (m), 125.6 (m), 123.8 (q, J = 272.2

Hz), 82.6, 82.4, 77.1, 76.5, 60.9, 57.5, 57.2, 44.8, 44.4, 43.2, 43.1, 30.9, 28.2, 14.2, 14.1.

+ HREI cald. for C22H24F3NO5 (M ): m/z 439.1607; found: m/z 439.1619.

Cycloadducts 118i

and 119i. Following

75 the above procedure with ethyl 4-trifluoromethylphenylpropiolate 117i (134.8 mg, 0.682 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 (152.3 mg, 0.629 mmol), the reaction was allowed to stir at 65oC for 120 hours. The crude product was purified by column chromatography (20% EtOAc in hexanes) to provide an inseparable mixture (68:32) of cycloadducts (74.5 mg, 0.170 mmol, 27%). Rf 0.28 (EtOAc:hexanes = 20:80); IR (neat,

-1 1 NaCl) 2981 (m), 1741 (s), 1710 (s), 1614 (m) cm ; H NMR (CDCl3, 400 MHz): δ 8.11-

8.04 (m, 2H), 7.65-7.63 (m, 2H), 4.79 (m, 1H), 4.65 (m, 0.68H), 4.60 (br s, 0.32H), 4.29-

4.20 (m, 2H), 3.41 (m, 1H), 3.31 (m, 1H), 2.11 (m, 1H), 1.73 (m, 1H), 1.51-1.50 (m, 9H),

13 1.35-1.30 (m, 3H); C NMR (APT, CDCl3, 100 MHz): δ 161.8, 161.7, 157.4, 157.2,

154.2, 153.7, 134.6, 132.3, 131.9, 131.6, 129.0, 125.6 (m), 123.7 (q, J = 272.7 Hz) 82.5,

82.4, 77.1, 76.5, 60.8, 57.5, 57.1, 44.9, 44.5, 43.3, 43.2, 30.8, 28.2, 14.2. HRESI calcd.

+ for C22H24F3NO5Na (M+Na) : m/z 462.1504; found: m/z 462.1523.

Cycloadducts 118j and

119j. Following the

above procedure with ethyl 2-heptynoate 117j (30.6 mg, 0.198 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene

97 (39.7 mg, 0.202 mmol), the reaction was allowed to stir at 65oC for 144 hours. The crude product was purified by column chromatography (30% EtOAc in hexanes) to provide an inseparable mixture (63:37) of cycloadducts (48.5 mg, 0.1304 mmol, 65%).

Rf 0.43 (EtOAc:hexanes = 30:70); IR (neat, NaCl) 2962 (m), 1712 (s), 1455(w), 1161 (s)

-1 1 cm ; H NMR (CDCl3, 400 MHz): δ 4.70 (m, 0.37H), 4.59 (m, 0.63H), 4.54 (m, 0.63H),

4.41 (m, 0.37H), 4.17-4.10 (m, 2H), 3.11 (m, 1H), 2.96 (m, 1H), 2.47-2.28 (m, 2H), 2.08

(m, 1H), 1.65 (m, 1H), 1.47 (m, 9H), 1.45-1.22 (m, 7H), 0.91-0.86 (m, 3H); 13C NMR

(APT, CDCl3, 100 MHz): δ 164.3, 163.7, 162.1, 157.4, 157.3, 131.8, 131.3, 82.2, 82.1,

77.2, 76.4, 76.3, 60.0, 57.6, 57.5, 56.8, 46.6, 44.9, 44.2, 42.9, 30.8, 30.7, 29.1, 28.8, 28.2,

+ 22.7. HRESI cald. for C19H29NO5 (M+H) : m/z 352.2124; found: m/z 352.2140.

Cycloadducts 118k and

119k. Following the

above procedure with ethyl cyclohexanepropynoate 117k (181.3 mg, 1.01 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (203.7 mg, 1.03 mmol), the reaction was allowed to stir at 65oC for 144 hours. The crude product was purified by column chromatography (20%

EtOAc in hexanes) to provide an inseparable mixture (67:33) of cycloadducts (104.6 mg,

0.277 mmol, 27%). Rf 0.31 (EtOAc:hexanes = 20:80); IR (neat, NaCl) 2978 (m), 2929

(s), 2853 (m), 1740 (m), 1712(s), 1646 (w), 1449 (m), 1335 (m), 1162 (m) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 4.65 (s, 0.33H), 4,56 (s, 0.67H), 4.49 (s, 0.67H), 4.40 (s, 0.33H),

4.14-4.07 (m, 2H), 3.04 (m, 1H), 2.96 (m, 1H), 2.74-2.69 (m, 1H), 2.10-2.07 (m, 1H),

13 1.68-1.58 (m, 6H), 1.45-1.44 (m, 9H), 1.28-1.01 (m, 8H); C NMR (APT, CDCl3, 100

MHz): δ 168.2, 167.6, 162,0, 157.3, 157.2, 129.9, 129.4, 82.1, 82.0, 77.0, 76.6, 59.9,

57.4, 57.1, 45.3, 43.8, 43.6, 42.5, 38.6, 38.4, 30.6, 30.5, 30.3, 30.2, 30.1, 28.1, 25.6, 25.5,

+ 25.4, 14.2. HRESI calcd. for C21H31NO5 (M ): m/z 377.2202; found: m/z 377.2210.

Cycloadducts 118l and 119l. Following the above procedure with 4-hydroxy-4-methyl-

2-pentynoic acid ethyl ester 117l (62.3 mg, 0.399 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (80.3 mg, 0.408 mmol), the reaction was allowed to stir

77 at 65oC for 144 hours. The crude product was purified by column chromatography

(gradient of 5-50% EtOAc in hexanes) to provide cycloadducts 118l (27.5 mg, 0.0778 mmol, 19%) and 119l (39.7 mg, 0.1123 mmol, 28%). Relative regio- and stereochemistry of each isomer was confirmed by various 2D NMR (COSY, HSQC,

HMBC) experiments and a gradient NOESY experiment preformed on a 400MHZ NMR spectrometer.

Cycloadduct 118l: Rf 0.30 (EtOAc:hexanes = 30:70); IR

(neat, NaCl) 3436 (br, s), 2978 (m), 2929 (w), 1709 (s), 1634

-1 1 (w), 1458 (w), 1369 (m), 1256 (w) 1160 (s), 1041 (m) cm ; H NMR (CDCl3, 400 MHz):

δ 5.18 (s, 1H), 4.69 (s, 1H), 4.46 (m, 1H), 4.26-4.13 (m, 2H), 3.12 (m, 1H), 3.04 (m, 1H),

2.17 (d, 1H, J = 11.5 Hz), 1.73 (d, 1H, J = 11.4 Hz), 1.48 (s, 9H), 1.35 (s, 3H), 1.32 (s,

13 3H), 1.28 (t, 3H, J = 7.1 Hz); C NMR (APT, CDCl3, 100 MHz): δ 171.3, 163.1, 157.2,

129.4, 82.5, 76.9, 70.6, 61.4, 56.8, 44.1, 43.4, 30.7, 28.5, 28.2, 27.7, 14.1. HREI calcd.

+ for C18H27NO6 (M ): m/z 353.1838; found: m/z 353.1831.

Cycloadduct 119l: Rf 0.23 (EtOAc:hexanes = 30:70); IR

(neat, NaCl) 3435 (br, s), 2977 (s), 2933 (m), 1709 (s), 1639

(m), 1459 (w), 1369 (m), 1161 (s), 1042 (s) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 5.16 (s, 1H), 4.61 (s, 1H), 4.52 (s, 1H), 4.23-4.15 (m, 2H), 3.09 (s,

1H), 3.00 (s, 1H), 2.15 (d, 1H, J = 11.5 Hz), 1.67 (d, 1H, J = 11.4 Hz), 1.46 (s, 9H), 1.31

13 (s, 3H), 1.27, (t, 3H, J = 7.1 Hz); C NMR (APT, CDCl3, 100 MHz): δ 171.7, 163.2,

157.4, 128.8, 82.4, 76.2, 70.5, 61.3, 57.2, 45.7, 42.1, 30.5, 28.4, 28.1, 27.6, 14.0. HREI

+ calcd. for C18H27NO6 (M ): m/z 353.1838; found: m/z 353.1849.

Cycloadducts 118m

and 119m.

Following the above procedure with alkyne 117m (53.2 mg, 0.207 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-

5-ene 97 (41.2 mg, 0.209 mmol), the reaction was allowed to stir at 65oC for 120 hours.

The crude product was purified by column chromatography (20% EtOAc in hexanes) to provide an inseparable mixture (63:37) of cycloadducts (48.3 mg, 0.106 mmol, 51%). Rf

0.29 (EtOAc:hexanes = 20:80); IR (neat, NaCl) 2958 (m), 2930 (m), 1712 (s), 1159 (m),

-1 1 1096 (m) cm ; H NMR (CDCl3, 400 MHz): δ 4.70 (s, 0.37H), 4.64 (s, 0.63H), 4.54 (s,

0.63H), 4.45 (s, 0.37H), 4.17-4.12 (m, 2H), 3.78-3.68 (m, 2H), 3.12 (m, 1H), 3.00 (m,

1H), 2.69 (m, 1H), 2.50 (m, 1H), 2.16 (m, 1H), 1.60 (m, 1H), 1.47 (m, 9H), 1.27-1.22 (m,

13 4H), 0.86-0.85 (m, 9H), 0.04-0.02 (m, 6H); C NMR (APT, CDCl3, 100 MHz): δ 162.2,

162.1, 161.5, 157.5, 157.3, 133.4, 132.8, 82.1, 77.0, 76.8, 60.5, 60.1, 57.5, 57.2, 47.3,

45.6, 44.7, 43.4, 33.2, 33.1, 31.0, 30.9, 29.7, 28.2, 25.9, 25.8, 18.3, 14.3, -5.3, -5.4.

+ HRESI calcd. for C23H39NO6SiNa (M+Na) : m/z 476.2444; found: m/z 476.2453.

Cycloadducts 118n and 119n. Following the above procedure with ethyl bromopropiolate 117n (180.4 mg, 1.02 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene

97 (603.6 mg, 3.06 mmol), the reaction was allowed to stir at 65oC for 120 hours. The crude product was purified by column chromatography (20% EtOAc in hexanes) and recrystallized (hexanes) to provide cycloadducts 118n (114.6 mg, 0.306 mmol, 30%) and

119n (79.6 mg, 0.213 mmol, 21%).

Cycloadduct 118n: Rf 0.26 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2980 (m), 1714 (s), 1615 (m) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 4.68 (m, 1H), 4.62 (m, 1H), 4.21 (q, 2H, J = 7.1 Hz), 3.31 (m, 1H),

2.06 (d, 1H, J = 11.8 Hz), 1.71 (d, 1H, J = 11.7 Hz), 1.47 (s, 9H), 1.29 (t, 3H, J = 7.1

13 Hz); C NMR (APT, CDCl3, 100 MHz): δ 160.3, 157.1, 138.6, 128.2, 82.6, 75.4, 60.9,

79 + 57.2, 52.2, 46.1, 30.5, 28.1, 14.1. HREI calcd. for C15H20 BrNO6 (M ): m/z 373.0525; found: m/z 373.0513.

Cycloadduct 119n: Rf 0.26 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2981 (s), 1713 (s), 1616 (s) cm-1; 1H NMR

(CDCl3, 400 MHz): δ 4.72 (s, 1H), 4.46 (s, 1H), 4.20-4.12 (m, 2H), 2.05-2.02 (m, 1H),

13 1.71-1.64 (m, 1H), 1.43-1.40 (m ,9H), 1.28-1.23 (m, 3H); C NMR (APT, CDCl3, 100

MHz): δ 160.1, 156.8, 138.9, 127.9, 82.5, 76.3, 60.7, 56.1, 50.7, 47.1, 30.4, 28.0, 14.0.

79 + HREI calcd. for C15H20 BrNO6 (M ): m/z 373.0525; found: m/z 373.0531.

Cycloadducts 118o and 119o. Following the above procedure with 1-bromo-2- phenylacetylene 117o (185.0 mg, 1.02 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene

97 (201.5 mg, 1.02 mmol), the reaction was allowed to stir at 65oC for 168 hours. The crude product was purified by column chromatography (gradient of 5-20% EtOAc in hexanes) to provide cycloadducts 118o (55.1 mg, 0.145 mmol, 14%) and 119o (41.5 mg,

0.110 mmol, 11%).

Cycloadduct 118o: Rf 0.37 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2977 (s), 1740 (s), 1704 (s), 1159 (s) cm-1; 1H

NMR (CDCl3, 400 MHz): δ 7.65-7.63 (m, 2H), 7.41-7.35 (m, 3H), 4.72 (s, 1H), 4.62 (m,

1H), 3.49-3.48 (m, 1H), 3.37-3.36 (m, 1H), 2.18 (d, 1H, J = 11.4 Hz), 1.72 (d, 1H, J =

13 11.5 Hz), 1.51 (s, 9H); C NMR (APT, CDCl3, 100 MHz): δ 157.3, 145.1, 131.3, 129.3,

128.7, 125.7, 109.1, 82.5, 76.7, 57.6, 51.5, 45.6, 30.8, 28.2. HREI calcd. for

79 + C18H20 BrNO3 (M ): m/z 377.0627; found: m/z 377.0613.

Cycloadduct 119o: Rf 0.34 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2977 (s), 1739 (s), 1704 (s), 1157 (s) cm-1; 1H

NMR (CDCl3, 400 MHz): δ 7.60-7.57 (m, 2H), 7.40-7.32 (m,

3H), 4.79 (s, 1H), 4.54 (s, 1H), 3.48-3.47 (m, 1H), 3.37-3.36 (m, 1H), 2.17 (d, 1H, J =

13 11.5 Hz), 1.72 (d, 1H, J = 11.5 Hz), 1.50 (s, 9H); C NMR (APT, CDCl3, 100 MHz): δ

157.2, 145.6, 131.2, 129.3, 128.7, 125.6, 109.2, 82.5, 77.1, 57.2, 50.3, 47.0, 30.8, 28.2.

79 + HREI calcd. for C18H20 BrNO3 (M ): m/z 377.0627; found: m/z 377.0616.

Cycloadducts 118p and 119p. Following the above procedure with 2-chloro-1- phenylacetylene 117p (140.3 mg, 1.03 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene

97 (204.8 mg, 1.04 mmol), the reaction was allowed to stir at 65oC for 96 hours. The crude product was purified by column chromatography (20% EtOAc in hexanes) to provide cycloadducts 118p (94.3 mg, 0.282 mmol, 27%) and 119p (82.4 mg, 0.247 mmol, 24%).

Cycloadducts 118p: Rf 0.28 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2977 (m), 1741 (s), 1702 (s), 1369 (s), 1159 (s)

-1 1 cm ; H NMR (CDCl3, 400 MHz): δ 7.58-7.56 (m, 2H), 7.40-

7.30 (m, 3H), 4.75 (m, 1H), 4.62 (s, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 2.18 (d, 1H, J =

13 11.5 Hz), 1.72 (d, 1H, J = 11.5 Hz), 1.51 (s, 9H); C NMR (APT, CDCl3, 100 MHz): δ

157.3, 141.1, 131.0, 129.0, 128.7, 126.0, 121.0, 82.4, 76.5, 57.8, 50.8, 42.8, 30.7, 28.2.

35 + HREI calcd. for C18H20 ClNO3 (M ): m/z 333.1132; found: m/z 333.1123.

Cycloadduct 119p: Rf 0.27 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2977 (s), 1740 (s), 1702 (s), 1369 (s), 1159 (s)

-1 1 cm ; H NMR (CDCl3, 400 MHz): δ 7.53-7.51 (m, 2H),

7.39-7.30 (m, 3H), 4.79 (m, 1H), 4.57 (d, 1H, J = 1.1 Hz), 3.35-3.31 (m, 2H), 2.18 (d,

13 1H, J = 11.5 Hz), 1.73 (d, 1H, J = 11.5 Hz), 1.50 (s, 9H); C NMR (APT, CDCl3, 100

MHz): δ 157.2, 141.6, 131.0, 129.0, 128.7, 126.0, 120.9, 82.0, 77.3, 57.0, 49.5, 44.3,

35 + 30.8, 28.2. HREI calcd. for C18H20 ClNO3 (M ): m/z 333.1132; found: m/z 333.1125.

Cycloadducts 118q and 119q. Following the above procedure with 1-(4- methylphenylthio)-1-hexyne 117q (207.8 mg, 1.02 mmol) and 3-aza-2- oxabicyclo[2.2.1]hept-5-ene 97 (204.8 mg, 1.04 mmol), the reaction was allowed to stir at 65oC for 120 hours. The crude product was purified by column chromatography

(gradient of 0-20% EtOAc in hexanes) to provide cycloadducts 118q (56.4 mg, 0.140 mmol, 14%) and 119q (17.8 mg, 0.044 mmol, 4%).

Cycloadducts 118q: Rf 0.49 (EtOAc:hexanes =

20:80); IR (neat, NaCl) 2959 (s), 2925 (s), 1740 (s),

-1 1 1701 (s), 1368 (s), 1161 (s) cm ; H NMR (CDCl3,

400 MHz): δ 7.27 (d, 2H, J = 8.1 Hz), 7.17 (d, 2H, J = 7.9 Hz), 4.35 (s, 1H), 4.06 (m,

1H), 2.92 (d, 2H, J = 7.1 Hz), 2.32 (s, 3H), 2.14 (d, 1H, J = 11.0 Hz), 2.10-1.97 (m, 2H),

1.57 (d, 1H, J = 11.1 Hz), 1.45 (s, 9H), 1.43-1.27 (m, 4H), 0.90 (t, 3H, J = 7.2 Hz); 13C

NMR (APT, CDCl3, 100 MHz): δ 157.2, 147.1, 138.2, 133.2, 131.5, 129.9, 127.9, 82.0,

77.3, 58.1, 47.8, 45.3, 30.7, 29.0, 28.2, 28.0, 22.8, 21.1, 13.8. HREI calcd. for

+ C23H31NO3S (M ): m/z 401.2025; found: m/z 401.2011.

Cycloadducts 119q: Rf 0.38 (EtOAc:hexanes =

20:80); IR (neat, NaCl) 2960 (s), 2930 (s), 1739 (s),

-1 1 1703 (s), 1368 (m), 1160 (s) cm ; H NMR (CDCl3, 400

MHz): δ 7.29-7.27 (m, 2H), 7.13-7.09 (m, 2H), 4.53 (s,

1H), 3.97 (s, 1H), 2.95-2.93 (m, 2H), 2.32 (s, 3H), 2.15 (d, 1H, J = 11.0 Hz), 2.07-2.00

(m, 2H), 1.61 (m, 1H), 1.39 (s, 9H), 1.36-1.22 (m, 4H), 0.92-0.87 (m, 3H); 13C NMR

(APT, CDCl3, 100 MHz): δ 157.1, 148.6, 138.0, 132.8, 130.8, 129.9, 128.1, 81.8, 77.8,

57.5, 47.1, 46.5, 30.7, 29.0, 28.1, 28.0, 22.7, 21.1, 13.8. HREI calcd. for C23H31NO3S

(M+): m/z 401.2025; found: m/z 401.2014.

Cycloadducts 118r and 119r. Following the above procedure with ethyl phenylethynyl sulfide 117r (166.2 mg, 1.02 mmol) and 3-aza-2-oxabicyclo[2.2.1]hept-5-ene 97 (204.5 mg, 1.02 mmol), the reaction was allowed to stir at 65oC for 144 hours. The crude product was purified by column chromatography (gradient of 5-20% EtOAc in hexanes) to provide cycloadducts 118r (35.1mg, 0.0976 mmol, 10%) and 119r (50.2 mg, 0.140 mmol, 14%).

Cycloadduct 118r: Rf 0.38 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2976 (m), 1739 (s), 1701 (s), 1161 (s) cm-1; 1H

NMR (CDCl3, 400 MHz): δ 7.30-7.25 (m, 4H), 7.17 (m,

1H), 4.71 (m, 1H), 4.45 (m, 1H), 3.33 (m, 1H), 2.93-2.73 (m, 2H), 2.15 (d, 1H, J = 11.2

Hz), 1.67 (d, 1H, J = 11.2 Hz), 1.46 (s, 9H), 1.32 (t, 3H, J = 7.4 Hz); 13C NMR (APT,

CDCl3, 100 MHz): δ 157.3, 139.1, 133.3, 132.9, 128.6, 127.4, 125.6, 82.3, 78.1, 57.8,

+ 45.7, 44.9, 31.1, 28.2, 25.8, 16.0. HREI calcd. for C20H25NO3S (M ): m/z 359.1555; found: m/z 359.1561.

Cycloadduct 119r: Rf 0.33 (EtOAc:hexanes = 20:80); IR

(neat, NaCl) 2977 (m), 1737 (s), 1700 (s), 1368 (s), 1160 (s)

-1 1 cm ; H NMR (CDCl3, 400 MHz): δ 7.31-7.27 (m, 4H),

7.17 (m, 1H), 4.64 (m, 1H), 4.52 (br s, 1H), 3.34 (m, 1H), 3.27 (m, 1H), 2.87-2.66 (m,

2H), 2.16 (d, 1H, J = 11.2 Hz), 1.66 (d, 1H, J = 11.2 Hz), 1.46 (s, 9H), 1.42-1.41 (m, 2H),

13 1.29 (t, 3H, J = 7.5 Hz); C NMR (APT, CDCl3, 100 MHz): δ 157.3, 138.6, 133.3,

128.6, 127.4, 125.6, 82.2, 77.5, 58.4, 47.0, 43.4, 31.0, 28.2, 25.9, 16.0. HREI calcd. for

+ C20H25NO3S (M ): m/z 359.1555; found: m/z 359.1564.

General procedure for oxidative ring opening reactions of the [2+2] cycloadducts. A

[2+2] cycloadduct (0.1-0.3 mmol, 1 equiv.) was added to an oven-dried vial and dissolved in an acetonitrile/water mixture (94:6). Mo(CO)6 (0.2-0.4 mmol, 1.1 equiv.) was then added to the reaction vial. The mixture was heated to 80oC. The crude products were purified by column chromatography (EtOAc – hexanes mixture) and concentrated in vacuo to give the corresponding [3.2.0] bicyclic product.

Ring-opened product 123. Following the above procedure

with cycloadduct 119c (131.9 mg, 0.328 mmol) and Mo(CO)6

(96.2 mg, 0.364 mmol), the reaction was refluxed at 80oC for 5

hours. The crude product was purified by column

84 chromatography (50% EtOAc in hexanes) to provide an [3.2.0] bicyclic product 123

(118.8 mg, 0.294 mmol, 90%). Rf 0.23 (EtOAc:hexanes = 50:50); IR (neat, NaCl) 3409

(br, s), 2977 (s), 1693 (s), 1603 (m), 1510 (s), 1257 (m), 1211 (m), 1176 (m) cm-1; 1H

NMR (CDCl3, 600MHz): δ 8.00 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 5.56 (br s,

1H), 4.37 (s, 1H), 4.25-4.20 (m, 3H), 3.79 (s, 3H), 3.47 (m, 1H), 3.36 (m, 1H), 2.77 (br s,

0.5H), 2.14 (br s, 1H), 1.82 (d, 1H, J = 14.7 Hz), 1.44 (s, 9H), 1.32 (t, 3H, J = 7.0 Hz);

13 C NMR (APT, CDCl3, 150 MHz): δ 162.9, 161.2, 158.8, 155.6, 130.9, 126.4, 124.9,

113.8, 79.5, 71.7, 60.1, 55.3, 52.3, 51.0, 50.1, 38.5, 28.5, 14.4. HREI cald. for

C22H29NO6 (M+): m/z 403.1995; found: m/z 403.1983.

Ring-opened product 124. Following the above procedure with

cycloadduct 119l (46.5 mg, 0.132 mmol) and Mo(CO)6 (40.3 mg,

0.153 mmol), the reaction was refluxed at 80oC for 5 hours. The

crude product was purified by column chromatography (80% EtOAc in hexanes) to provide an [3.2.0] bicyclic product 124 (33.5 mg, 0.0943 mmol, 71%). Rf

0.39 (EtOAc:hexanes = 80:20); IR (neat, NaCl) 3415 (s), 2977 (s), 1686 (s) cm-1; 1H

NMR (CDCl3, 600 MHz): δ 5.42 (d, 1H, J = 8.7 Hz), 5.37 (s, 1H), 4.34 (br d, 1H, J = 3.6

Hz), 4.24 (q, 2H, J = 7.1 Hz), 4.11 (br s, 1H), 3.24-3.16 (m, 2H), 2.22-2.15 (m, 1H), 1.84

13 (d, 1H, J = 14.8 Hz), 1.43 (s, 9H), 1.33-1.29 (m, 9H); C NMR (APT, CDCl3, 150

MHz): δ 171.0, 163.9, 155.2, 133.3, 82.3, 70.9, 70.5, 61.3, 54.0, 50.7, 49.2, 38.2, 28.6,

28.5, 27.7, 14.2. HREI cald. for C18H29NO6 (M+): m/z 355.1995; found: m/z 355.1987.

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